Immunotherapy has improved melanoma patient survival but unfortunately many patients still progress despite these treatments. Thus, a better understanding of the immune cells determining the anti-cancer response that occur when immunotherapy is effective is necessary to improve patient outcomes. Preliminary data (2019) from a collaboration between the Molecular Oncology Group at CRUK Manchester Institute and the Melanoma Team at The Christie NHS Foundation Trust have identified blood immune cells that are associated with treatment response, and thus appear very promising as prognostic biomarkers.
This project (Single cell analysis of prognostic T-Cell subsets) aims to perform an in-depth characterisation of this and other cell subsets which may be involved in cancer response, to identify new blood based biomarkers for personalised medicine and potential therapeutic targets.
The big change towards the close of 2018 was the approval of adjuvant therapy for intermediate and high risk melanoma. Two treatment regimens: dabrafenib and trametinib for BRAF positive patients with resected Stage 3 disease, and nivolumab for all patients with resected Stage 3 and 4 disease.
Furthermore, pembrolizumab was approved by NICE (National Institute for Health and Care Excellence) prior to approval by the EMA. Notably, this was the first time that NICE approved a drug before EMA. Pembrolizumab is approved for intermediate and high risk Stage 3 disease. These treatments are associated with a 40-45% reduction in the risk of recurrence. They are already standard of care, and are yet another example of the huge advances made in the last eight years.
The UK was a major contributor to the study (KEYNOTE 054) which showed a clear benefit of pembrolizumab in reducing the risk of recurrence after surgery for melanoma.
Health Secretary Matt Hancock announced the completion, on 05/12/2018, of the 100,000 Genome Project. The ground-breaking programme began in 2012 with the aim of 'decoding' that number of genomes. A genome contains all of the information needed to build, grow and develop an organism. By understanding these genomes it is hoped researchers will then have the knowledge to uncover new diagnoses and improve treatments for patients with rare inherited diseases and cancer.
The melanoma team here in Manchester were part of this ground-breaking project to make the UK world leaders in genomic medicine. With Prof Marais at the CRUK Manchester Institute and colleagues at the Royal Marsden Hospital, Prof Lorigan was leading the UK Melanoma Group project linked to the 100,000 Genome Project being run by Genomics England Clinical Interpretation Partnership. Whole genome sequencing (WGS) was performed on hundreds of melanoma patient samples linked to new treatments and rare melanoma subtypes. WGS is the most detailed molecular analysis possible, allowing us to look at all of the genes in the tumour and compare them to the patients’ normal tissue. It essentially representing the blueprint for the functioning of a cell. With this, we expect to uncover new clues on how melanoma develops and how to treat it.
The 100,000 Genome Project was one of the biggest WGS projects in the world. The genetic material came from cancer patients, patients with rare diseases (and two of their blood relatives) and also some patients with severe infections. A massive database will now be available for treatment and research with the intended outcome of better diagnostic capabilities and more effective and personalised treatments.
Dr. Rebecca Lee (molecular oncology group) has won the Association of Cancer Physicians McElwain translational research prize for “Circulating tumour DNA as a tool to guide clinical decision making in melanoma”. These annual awards were established by the friends and colleagues of Professor Tim McElwain to commemorate his extraordinary contribution to the development of Medical Oncology in the UK. Rebecca was awarded the prize at NCRI's annual conference in November 2018. The award presentation followed hot on the heels of her passing her PhD viva that same month!
September 2018 was a successful month for Dr. Sara Valpione (Molecular Oncology Group. She received a Career Development Award from the Harry J Lloyd Charitable Trust. In collaboration with Professors Lorigan and Marais she will lead a translational research project aiming to study the mechanisms of response and resistance to immunotherapy, with the purpose to improve the treatment of melanoma. The research will be possible thanks to the participation of consenting melanoma patients from The Christie who will donate blood and biopsy samples.
Dr. Valpione was also awarded one of the five EORTC Early Career Investigator Melanoma Translational Research grants available for 2018. The €50,000 received with the grant will fund a translational research in collaboration with CRUK Manchester Institute to investigate the melanoma micro-environment changes that contribute to response or resistance to immunotherapy.
Congratulations on these prestigious awards!
Dr. Valpione has previously received an award from ASCO in June 2017 and special recognition from her University in December 2017. Padua University selected only three 'Alumni of the Year' with an excellent track record in their discipline, with Dr. Valpione's being the only one in science/medicine.
In April 2018 Professor Paul Lorigan was selected as the new secretary and next Chair of the EORTC Melanoma group. This is one of the largest melanoma networks in the world, and conducts clinical trials and translational research in the melanoma field. Its objectives are to improve clinical care of patients suffering with cutaneous or ocular melanoma, and to increase knowledge about melanoma acquisition and progression.
To be invited to take on this role recognises both the contribution of the individual to the EORTC and the area of melanoma research, and also the importance of The Christie and the CRUK Manchester Institute in fostering the collaboration of immunologists, pathologists and clinicians.
The Royal Society is the oldest independent scientific academy and to be recognised as a Fellow is one of the greatest accolades for scientists. Professor Richard Marais has been elected as a Fellow in 2018 for his dedication to promoting excellence in science in the field of melanoma.
Prof. Marais was presented with the Outstanding Research Award by the Society for Melanoma Research in Brisbane during the annual SMR conference in October 2017. This honour is to recognise an individual or group for highly impactful, major discoveries in the field of melanoma within the last five years.
Disappointing results from a Phase III study (ECHO 301) which was stopped early due to futility. Epacadostat is an oral treatment that appears to make the tumour microenvironment less hostile to the cells of the immune system.
Preliminary results from an early Phase Study showed that when this was combined with immunotherapy, the response rates were much higher than with immunotherapy alone, but the side effects were modest. However a definitive study comparing pembrolizumb + epacadostat vs. pembrolizumab alone was stopped early by the Independent Data Safety Committee as there was no clear benefit to the new combination.
We need to spend some time studying the results to try to understand why the study was negative after such a strong initial signal.
The Molecular Oncology Group have moved to a new site at Alderley Park. This is only a temporary move until they return to the redeveloped Paterson site in 2021. These are the plans:
"An ambitious, world-class cancer research facility is to be built at The Christie on the site of the Paterson building which suffered devastating fire damage in April 2017 displacing over 300 scientists and support staff.
It will integrate researchers and clinicians in a new state-of-the-art building, who will develop new ways to conduct team science approaches to accelerate the translation and adoption of research into the clinic.
This approach will ensure that Manchester remains at the international forefront of research in this field - understanding and tackling the diversity and complexity of cancer to drive better outcomes for patients with the very latest discoveries and breakthroughs."
This text is taken from the Manchester University website about the new world-class cancer centre.
Dr Santiago Zelenay, a melanoma team member at the CRUK Manchester Institute received Cancer Research UK’s Future Leader Prize at the NCRI Cancer Conference in Liverpool in November 2017.
He is an immunologist who is building an exciting research programme looking at the cellular and molecular mediators that regulate anti-cancer immunity. His discovery that prostaglandin E2 production by cancer cells enables immune escape has raised exciting new ideas for targeted approaches adjuvant to immunotherapy.
He said: “I am extremely honoured and grateful to Cancer Research UK and the panel for selecting me for this prestigious award. I feel very proud to be now part of a list of awardees that includes so many distinguished and accomplished investigators. In a way, given that the prize is for “Future” Leaders in Cancer Research I cannot also help but feel that the pressure is really on. I hope to live up to expectations.”
The Future Leaders in Cancer Research Prize recognises researchers who have produced research of international importance within 10 years of receiving their doctorate, and proved themselves capable of becoming leaders in the field.
To read the full version of this article go to MCRC news page.
We have made huge progress in the treatment of patients with advanced melanoma in the last six years with the advent of targeted therapy and immunotherapy. For patients suitable for both treatments, we do not know which treatment to start first. There is emerging evidence that if you start with targeted therapy, it makes the tumour more responsive to immunotherapy. But we don’t know when to switch from one treatment to another.
We have shown that with a blood test, we can pick up circulating tumour DNA (ctDNA), which is tumour genetic material released from the tumour in to the blood. We can use this to monitor the response to treatment. We are now about to start the CACTUS study in which we will monitor patients on targeted therapy with dabrafenib and trametinib using ctDNA, and switch them to immunotherapy at the point when they are most likely to benefit. This is the first study of its kind in melanoma to use a biomarker to individualise/personalise treatment decisions in real time in patients on treatment, and we think it is a major advance. The study will initially run in four centres in the UK (Newcastle, Mount Vernon, Royal Marsden and Manchester) in February 2018, with a view to expanding internationally if we get a strong signal that it works. We are very excited about this technology and are looking to use it in a number of other ways to individualise advice and treatment decisions. More information to follow in the next few months.
Two of our young investigators have been honoured with a Conquer Cancer Foundation ASCO merit award at the Annual meeting in Chicago in June 2017. Only 12 abstracts are selected for presentation and discussion in this category so for both of them to achieve this is a huge honour. Well done and thanks to everyone that made this possible, it’s a real team effort.
Dr. Sara Valpione’s award was for her work leading an international group of collaborators in Europe, US and Australia, looking at retreatment of melanoma patients with targeted therapy. ‘Re-challenge with BRAF directed treatment: a multi-institutional retrospective study’. During the discussion it was recognised that the study results are expected to change practice and have a major impact on how patients are treated in the future.
Dr. Rebecca Lee’s work looked at blood borne biomarkers that can predict the risk of relapse in patients who have had curative surgery for melanoma. 'Use of circulating tumour DNA to predict survival in patients with resected high-risk stage II/III melanoma'. These preliminary data showed that if we test for a mutation in the blood that comes from the cancer (a "liquid biopsy") following surgery for high risk, early stage melanoma, if the mutation is detected then patients are at extremely high risk of relapse. This information can then be used to potentially identify early those patients in whom we might need to follow up more closely or to potentially consider more intensive treatment.
The study results have just been presented at the America Association of Cancer Research (AACR) meeting in Washington. This compared single agent with combination immunotherapy in people where melanoma has spread. We now know that combination therapy is a more effective treatment for many patients, and will be able to use these results to advise patients accordingly. However there remain a number of unanswered questions about how best to select those who need this treatment as many patients do just as well with one drug. The combination of two drugs is associated with significantly more toxicity.
Following on from discussions with NHS England, we have now resolved the issue about access to combination immunotherapy and targeted therapy for all eligible patients. Patients in the UK now enjoy better access than many other countries in Europe, and this is a testament to close discussion and interaction between senior UK clinicians and NHS England.
Three major new treatments have been approved by NICE and are currently funded by the Cancer Drugs Fund. The targeted therapy combination of dabrafenib and trametinib is suitable for patients with a BRAF mutation (approximately 50% of all patients) and is a significant advance over the previous standard of care. The immunotherapy combination of ipilimumab and Nivolumab is also appropriate for many patients. We are still awaiting the final results of trials but this is also set to become a standard of care for many patients.
The third treatment is TVEC, an injected treatment for patients where the melanoma has not spread to internal organs. Whilst there are a relatively limited number of patients who will be suitable for TVEC, the real excitement is that TVEC combined with other treatments seems to be very effective, and trials are ongoing to evaluate this further. So the last three months will be seen as a major turning point for access to treatment and improved outcomes for patients in the UK.
A recent British Journal of Healthcare ‘Comment’ article written by two of the team here in Manchester, Dr Fabio Gomes and Professor Paul Lorigan provides a succinct overview of the present state of melanoma management, treatment options and potential future directions for both melanoma and other cancers responsive to these treatments. Access PDF here.
The research programme in melanoma continues a pace, focusing on developing Personalised Medicine approaches to managing patients with melanoma. The aim is to analyse each individuals melanoma sample at a detailed molecular level before treatment, then monitor the patient closely on treatment using ‘liquid biopsies’ – highly sophisticated blood tests that can detect parts of the tumour DNA in the blood - to pick up at an early stage any changes in the tumour that suggest it is responding or becoming resistant to treatment. We have published our findings in the journal Cancer Discovery (Girotti et al, December 2015) and have a second paper accepted for publication, and have given presentations at a number of international meetings including the America Association for Cancer Research in April 2016. At present, we are continuing to evaluate this in clinical trials, with the plan to move it to standard of care as soon as possible.
Doctor Andrew Hudson and Doctor John Brognard (CRUK Manchester Institute) have shown that many of the current techniques used to search for cancer causing genes can miss their intended targets due to 'cold spots' that are skipped by these methods. This discovery will have major implications for how we do this type of research. Read the summary here.
Discrepancies in Cancer Genomic Sequencing Highlight Opportunities for Driver Mutation Discovery. Hudson AM, Yates T, Li Y, Trotter EW, Fawdar S, Chapman P, Lorigan P, Biankin AV, Miller C, Brognard J.Cancer Research. 2014 Sep 25. [Epub ahead of print]
Dr Amaya Virós, a clinician scientist based at the Cancer Research UK Manchester Institute, has been awarded a Wellcome Trust Intermediate Clinician Scientist Fellowship. The fellowship will allow Dr Virós to establish her own lab to carry out research into why older patients are less likely to survive following a melanoma diagnosis.
Dr Virós explains her project: “More than 80% of melanoma deaths occur in patients who are older than 50 years old, and mortality is specifically increasing in the elderly. Melanoma in the elderly is also more likely to progress. We will investigate why older people are more vulnerable to melanoma and if melanoma in the elderly is inherently more aggressive.”
Professor Marais, Director of the CRUK Manchester Institute, said: “The award by the Wellcome Trust is a reflection of her impressive achievements to date and her potential as a world-leading cancer researcher.”
Metastasis is responsible for most of the cancer-related deaths and, among common tumour types melanoma is one with great potential to metastasize. It is critical to understand the mechanisms that mediate this process. This study used detailed epigenomic methods which analyse changes to all a cell's genetic material, combined with laboratory (in vitro) and melanoma patients' (in vivo) data. From this a protein was identified which exacerbates melanoma growth both in vitro and in vivo. Coincidentally it also confers more sensitivity of the tumour to targeted therapy. In the clinical setting, finding molecular biomarkers for predicting whether metastatic disease will develop or for determining prognosis is a huge advantage when selecting and developing treatments and planning patient care.
Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR. Vizoso M, Ferreira HJ, Lopez-Serra P, Carmona FJ, Martínez-Cardús A, Girotti MR (pictured), Villanueva A, Guil S, Moutinho C, Liz J, Portela A, Heyn H, Moran S, Vidal A, Martinez-Iniesta M, Manzano JL, Fernandez-Figueras MT, Elez E, Muñoz-Couselo E, Botella-Estrada R, Berrocal A, Pontén F, Oord JV, Gallagher WM, Frederick DT, Flaherty KT, McDermott U, Lorigan P, Marais R, Esteller M. Nat Med. 2015 Jun 1. doi: 10.1038/nm.3863. [Epub ahead of print]
Promising early data from a new drug developed by the CRUK Manchester Institute in collaboration with the Institute for Cancer Studies (Royal Marsden Hospital) and the Wellcome Foundation led to a publication in Cancer Cell 2015.
We were greatly encouraged by the results, and so with a£280,000 grant from our Melanoma Research Fund this new panRAF inhibitor is being trialled here and at the Royal Marsden Hospital. The first patient began their treatment in April 2015 at The Christie. Read the Cancer Cell summary here: Paradox breaking RAF inhibitors.
Uveal melanoma is a rare form of eye cancer. Until now there has been no national guidance for its treatment. These new guidelines were developed over three years by an independent group (including clinicians and patients). The National Institute for Health and Care Excellence (NICE) has approved these guidelines. NICE provides guidance and advice to improve health and social care nationally.
Melanoma Focus funded the project, read more about the Uveal Melanoma Guidelines Project.
The results of the 'COMBI-V' trial were published in the New England Journal of Medicine on November 16th 2014. Dr. Lorigan was the Principal Investigator for this international study. The results showed definitively that a combination of BRAF and MEK inhibitors is superior to BRAF inhibitor alone (for patients suitable for targeted therapy with a BRAF inhibitor).
Combination therapy is licensed in the US but not yet in Europe. However, the good news is we are able to offer this treatment to patients by way of a 'Compassionate Use Programme'. This programme is established in the European Union for patients who have a disease with no satisfactory authorised therapies or who cannot enter a clinical trial. It is a way for them to access new treatment options under development.
Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D. New England Journal of Medicine. 2014 Nov 16. [Epub ahead of print]
Professor Richard Marais and colleagues at the Cancer Research UK Manchester Institute have shown conclusively that UV light (ultraviolet) causes melanoma. Importantly, sunscreen protection reduces the risk but not completely. This further highlights the importance of also wearing protective clothing and a sun hat. The research was published in the most prestigious scientific journal Nature and received wide press coverage.
Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53. A. Viros, B. Sanchez-Laorden, M. Pedersen, SJ. Furney, J. Rae, K. Hogan, S. Ejiama, M. Girotti, M. Cook, N. Dhomen & R. Marais. Nature 511, 478-482 (24 July 2014)
The results of a two year Manchester based study looking at the emotional impact of a diagnosis of melanoma have been published in two journals. 'Asc Me' was funded entirely by the Melanoma Research Fund. As a result of the study we will be able to improve our identification of those people most at risk of anxiety and depression and offer them the appropriate support.
Prevalence and correlates of unmet supportive care needs in patients with resected invasive cutaneous melanoma. Molassiotis A, Brunton L, Hodgetts J, Green AC, Beesley VL, Mulatero C, Newton-Bishop JA, Lorigan P. Annals of Oncology. 2014 Oct;25(10):2052-8.
Assessing the impact of diagnosis and the related supportive care needs in patients with cutaneous melanoma. Stamataki Z, Brunton L, Lorigan P, Green AC, Newton-Bishop J, Molassiotis A. Support Care Cancer. 2014 Sep 5. [Epub ahead of print]
Scientific Papers' Summaries: for non-specialist and specialist readers
The latest relevant research papers can be viewed here. They are summarised and 'translated' into non-academic language. Summaries of important publications.