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6th December 2024
The Covid-19 pandemic boosted advancing technology to create vaccines incorporating messenger RNA. Professor Alain Astier discusses how these vaccines have further potential to be rapidly tailored to target oncogenic profiles and provide significant benefits in personalising cancer treatment.
Edward Jenner’s pioneering work in his 1801 treatise On the Origin of the Vaccine Inoculation and the first successful vaccination against smallpox heralded the development of vaccine therapy from the second part of the 19th century onwards.
One area in which exciting progress has been made is in immunotherapy and the development of cancer vaccines including messenger RNA (mRNA) variants. Unlike traditional immunisation, the situation in cancer is more complex. It requires sophisticated approaches to develop appropriate vaccines as the cancer cells more closely resemble normal, healthy cells than bacterial or fungal allergens do.
The first preventive cancer vaccine, against hepatitis B virus-induced hepatocarcinoma, was launched in 1982. Other preventive vaccines, such as those against human papillomavirus, are currently in use.
There are four main types of therapeutic cancer vaccines:
1. Cell-based vaccines
Cell-based cancer vaccines use all the antigens expressed by tumour cells: tumour-associated antigens (TAAs) and tumour-specific antigens (TSAs).
TAAs, such as HER2/neu, are self-proteins (antigens originating within the body) abnormally overexpressed by cancer cells. TSAs are antigens specific to some tumour cells, such as mutated Kras or β-catenin.
In cellular cancer vaccines, cultured cells from tumour cell banks are injected globally to provoke the immune response, similar to classic vaccination, or incubated with cultured dendritic cells. The dendritic cells present the antigens to T lymphocyte CD4+ helper and CD8+ cytotoxic cells, which induces activation, multiplication and migration into the tumour through the lymphatic system.
Cancer cell cultures can also liberate soluble TAAs or TSAs into the culture media, which can be injected as an alternative to the cells.
‘Antigenic essence’ technologies comprise a target fraction of cellular antigens, the composition of which is precisely controlled by mass spectrometry. Antigenic essence technology makes it possible to update many existing cellular vaccines and to develop new ones, thereby introducing a further direction for anticancer vaccine research.
2. Viral-based vaccines
Viral-based cancer vaccines use engineered viruses as vectors to deliver tumour antigens to the immune system. This requires virus proliferation and requires complex and potentially hazardous handling.
3. Peptide-based vaccines
Peptide-based cancer vaccines stimulate the immune system using antigenic peptides corresponding to cancer epitopes of interest. These antigenic peptides can be produced via fractionating larger antigen proteins or by bioengineering after the DNA sequences coding for them are identified.
4. Nucleic acid-based vaccines
Nucleic acid-based cancer vaccines utilise DNA or RNA to encode tumour antigens that are presented to the immune system using various delivery platforms such as liposomes or nanoparticles. A typical nucleic acid vaccine is the mRNA Covid-19 vaccine. Although designed to fight a non-oncogenic virus, it provoked much interest in the potential of mRNA vaccine technologies in cancer.
At the industrial level, the production of cancer vaccines is a complex process. Indeed, mass culture, which requires trypsinisation to detach the adherent cells, all under strict aseptic conditions, is complicated and expensive.
In the case of personalised vaccines, the cancer cells are derived from individual patients, and the industrial-scale production of cellular-based vaccines can, again, be complex and challenging. However, production at the local level, such as within hospitals, could be encouraged.
The production of peptide-based vaccines is more affordable. Mass production of peptides via automation does not require cell culture; it only involves sequencing of the DNA coding for the protein or peptides of interest.
The principle is to obtain a tumour sample from an individual patient or a cancer cell bank to establish a DNA mutation map compared to healthy cells from the same patient or from normal cells and the organ of origin. The map is used to identify the corresponding DNA sequence of numerous tumour antigens and to synthesise the corresponding peptides. However, this approach requires producing and purifying large quantities of peptides.
Problems with protein or peptide handling, such as aggregation or instabilities, frequently occur and require substantial expertise. Moreover, these foreign peptides can also induce severe allergic responses.
A more innovative approach is theoretically to inject the corresponding mRNAs directly, which ‘orders’ the synthesis of corresponding peptides by the patient’s cells with good efficiency and safety.
Thus, after identifying the DNA sequence coding for the antigenic peptides and combining it with today’s methods for nucleic acid synthesis, it is straightforward to produce sufficient mRNA.
However, a severe limitation previously was significant instability and poor intrinsic cellular penetration due to the very polar nature of the mRNA. Moreover, simple mRNAs are recognised as foreign substances and are rapidly eliminated from the body.
Thanks to the 2023 Nobel Laureates Katalin Karikó and Drew Weissman, whose pivotal discoveries concerning nucleoside base modification enabled the development of effective mRNA vaccines against Covid-19, it is now possible to overcome the underlying instability of engineered mRNAs.
State-of-the-art mRNA constructs confer many improvements regarding purification, the structure and length of untranslated regions, regulatory elements and modifications of coding sequences.2 For example, replacing uridine bases with pseudouridine in an mRNA sequence dramatically improves the yield of the corresponding protein.1
Using nano-delivery systems can overcome the difficulties in transporting and encapsulating these custom-made mRNAs into cells.3,4 These include lipid-based nano vectors, such as liposomes or lipoplex particles, and dendrimer polymer nano vectors, which are often commercially available or easily manufactured.5
Moreover, mRNAs can also be vectorised by viruses or polypeptides rich in arginine, which neutralise very polar polynucleotides and facilitate penetration through the cell membrane.
The main benefits of the mRNA approach to producing vaccines are the ease of manufacture on an individual scale, the lack of need to handle viruses or perform cell culture, the lack of complex protein production, and very rapid processes that are less expensive than those for classical vaccines.
Thus, small-scale units such as academic facilities can easily produce personalised vaccines. Several mRNAs coding for several cancer antigens can be administered simultaneously. The rapidity of obtaining mRNAs could also permit adapting the vaccine to the evolution of the tumour in terms of neoantigen expression. Furthermore, an excellent tolerance has been demonstrated in several clinical trials as an mRNA vaccine is, per se, non-immunogenic.
mRNAs can also help promote the production of a corresponding antibody by the host B cells. In this case, the idea is to replace the repetitive administration of a large quantity of a monoclonal antibody with a single injection of its corresponding mRNA.
As demonstrated by Pardi and colleagues, a single injection of the mRNAs that encode the VRC01 monoclonal antibody against HIV surface protein led to robust production of this antibody protein in the livers of mice within 24 hours.6 A weekly injection was enough to maintain high levels of circulating VRC01 antibodies.
This approach could also benefit by dramatically simplifying the production of anticancer monoclonal antibodies, making it achievable at the hospital level.
From the pioneering work with mRNA anti-Covid vaccines, mRNA therapeutic vaccines are now regarded as an attractive and promising alternative to conventional vaccines for transmissible diseases and cancers.7,8
Although most of these cancer vaccines are still experimental, some have shown promising results in clinical trials, with positive responses in shrinking tumours and improving patient survival.
Alain Astier PharmD PhD
Honorary head of the Department of Pharmacy, Henri Mondor University Hospital, and French Academy of Pharmacy, Paris, France
1 Karikó K et al. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 2005;23,(2):165–75.
2 Duan L-J et al. Potentialities and Challenges of mRNA Vaccine in Cancer Immunotherapy. Front Immunol 2022;13:923647.
3 Liu T, Liang Y, Huang L. Development and delivery systems of mRNA vaccines. Front Bioeng Biotechnol 2021;9:718753.
4 Hou X et al. Lipid nanoparticles for mRNA delivery. Nat Rev Mater 2021;6(12):1078–94.
5 Campani V et al. Lipid Nanovectors to Deliver RNA Oligonucleotides in Cancer. Nanomaterials 2016;6(7):131.
6 Pardi N et al. Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge. Nat Commun 2017;2:8:14630.
7 Jackson NAC et al. The promise of mRNA vaccines: a biotech and industrial perspective. npj Vaccines 2020;5:11.
8 Li Y et al. mRNA vaccine in cancer therapy: Current advance and future outlook. Transl Med 2023;13:e1384.
7th October 2024
Dr João Gonçalves PhD provides expert commentary on a recent study demonstrating real-world evidence of the feasibility and efficacy of a personalised peptide vaccine for glioblastoma – one of the most malignant primary brain tumours in adults.
The goal for cancer vaccines is straightforward: to harness what has been achieved for infectious diseases and their antigens to focus the immune system on eradicating cancer cells.1
A better understanding of the range of tumour-associated antigens and technological advances in neoantigen prediction, in vivo genetic and pharmacological models, and spectroscopic methods have facilitated improved designs for therapeutic cancer vaccines over the last decade.2,3
Despite these developments, glioblastoma remains one of the most formidable challenges in oncology, with current treatment modalities offering limited survival benefits. Regardless of advances in surgery, radiotherapy and chemotherapy, the prognosis for glioblastoma patients remains poor, with nearly all patients experiencing recurrence.
Previous studies for glioblastoma therapeutic vaccines have suggested that few neoantigens could be targeted in glioblastoma due to low mutation burden. However, a recent study by Latzer and colleagues offers real-world evidence and a promising glimpse into the potential of personalised peptide vaccines targeting tumour-specific neoantigens to extend survival in glioblastoma patients.3
This retrospective study involved 173 patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma, treated with a personalised neoantigen-derived peptide vaccine between 2015 and 2023.3
The personalised approach, tailored to the specific somatic mutations within each patient’s tumour, aims to harness the immune system by inducing a targeted T-cell response against the tumour. The median overall survival (OS) for the entire cohort was 31.9 months – a notable improvement compared with the historical median of approximately 15 months observed with the current standard of care.
The importance of this study lies in its demonstration of the feasibility, safety and potential efficacy of such personalised vaccines in a real-world setting.
The ability to generate a vaccine within 16 weeks of tumour tissue acquisition and observe a robust immune response in 88% of the patients underscores the practicality of this approach. Moreover, the study shows a clear correlation between the strength of the vaccine-induced immune response and patient survival, with those exhibiting multiple vaccine-induced T-cell responses achieving a median OS of 53 months.
This study provides compelling evidence for clinicians and researchers that personalised peptide vaccines could significantly advance the treatment of glioblastoma. The fact that most patients tolerated the vaccine well, with only grade 1 or 2 adverse events, suggests that this approach could be integrated into clinical practice without adding undue toxicity.
However, the study also highlights several challenges. First, the heterogeneity of the patient population, including primary and recurrent glioblastoma cases, introduces variability that could confound the interpretation of results. Additionally, the study’s retrospective nature and the absence of a randomised control group limit the ability to draw definitive conclusions about the vaccine’s efficacy relative to standard therapies.
The study’s reliance on patients who could afford the cost of the vaccine and travel to Germany introduces a potential socio-economic bias, which may limit the generalisability of the findings.
The study’s focus on the immunogenicity of personalised vaccines provides valuable mechanistic insights. The detection of vaccine-induced T-cell responses in most patients and the association of these responses with prolonged survival support the hypothesis that effective anti-tumour immunity can be achieved through personalised vaccination strategies.
This is particularly relevant in glioblastoma, a tumour type often considered immunologically ‘cold’ due to its low mutational burden and immunosuppressive microenvironment.
Moving forward, exploring the factors contributing to variability in patients’ immune responses will be critical. The study noted that 10% of patients did not mount a detectable T-cell response, which raises questions about the potential barriers to effective immunisation in these individuals. Understanding the role of factors such as the tumour microenvironment, immune checkpoint expression and patient-specific immunogenetic factors will be essential in refining this approach.
Additionally, the study opens the door to further exploration of combination therapies. The observation that adding bevacizumab, a vascular endothelial growth factor inhibitor, was associated with reduced survival suggests that careful consideration is needed when integrating personalised vaccines with other therapies. Combining immune checkpoint inhibitors or other immune response modulators to enhance the vaccine’s efficacy may be beneficial.
The promising results of this real-world study set the stage for prospective, randomised clinical trials that can more rigorously assess the efficacy of personalised neoantigen vaccines.1,2,4 Such trials should aim to control for the heterogeneity seen in this study by focusing on more homogeneous patient populations. Moreover, they should investigate the optimal timing and sequencing of vaccine administration relative to other treatments, such as surgery, radiotherapy and chemotherapy.
Given the significant resources required for the development of personalised vaccines, future efforts should also focus on streamlining the production process. Advances in next-generation sequencing and bioinformatics will be vital in reducing the time and cost associated with vaccine development, making this approach more accessible to a broader patient population.5,6
Another critical area of investigation will be the long-term immune monitoring of patients who respond to the vaccine.7 The durability of the immune response and its ability to prevent recurrence in the long term are essential considerations for the overall success of this treatment strategy. The study’s indication that vaccine-specific T-cells can persist and continue to provide protection suggests that long-term benefits may be achievable.
The study by Latzer et al represents a significant step forward in the development of personalised cancer immunotherapies.3
Demonstrating the feasibility and potential efficacy of neoantigen-targeted peptide vaccines in a real-world setting provides a foundation for future clinical trials that could transform the treatment landscape for glioblastoma and potentially other solid tumours.
However, as with any pioneering approach, further research is needed to address the challenges and refine the strategies that will enable the widespread adoption of this promising therapeutic modality. If successful, personalised peptide vaccines could offer a new avenue of hope for patients with glioblastoma, a disease that has long been synonymous with poor prognosis.
João Gonçalves PharmD PhD
Faculty of Pharmacy, University of Lisbon, Portugal
27th September 2024
The idea of cancer vaccines is not new, but Dr Victoria Kunene, consultant medical oncologist at Queen Elizabeth Hospital Birmingham, UK, is leading the charge in their latest iteration: personalised preventative and therapeutic mRNA vaccines against colorectal cancer. With an introduction from Helena Beer, Dr Kunene shares first-hand insights into the clinical trial, the NHS Cancer Vaccine Launch Pad initiative and their potential for revolutionising patient care.
Ask Dr Victoria Kunene why she wanted to specialise in oncology and her answer won’t be too dissimilar to the one she gave 15 years ago interviewing as a registrar: it’s the opportunity to help a unique patient group navigate an extremely challenging period in their lives and, where possible, give them extra time to spend with loved ones and achieve their goals.
‘Just being part of that journey and helping someone through a difficult time is humbling,’ she says. ‘It’s not easy, but it’s satisfying. You feel like you have positively contributed at a crucial time.’
While Dr Kunene’s drive, empathy and ambition have remained constant during her career, one thing that’s changed during the intervening years is the means by which she is able to help due to a ‘constant stream of new information and new treatments’ coming through the clinical development pipeline.
‘Treatment has advanced since my oncology registrar years – we’ve made some progress,’ she confirms. ‘Everyone would probably blow their trumpet about their own field, but [oncology is] the one field whereby science meets clinical practice so completely.’
As a senior house officer (SHO), it was gastroenterology that sparked Dr Kunene’s interest and it was this, as well as working with ‘a brilliant team’ at Wansbeck General Hospital in Northumberland, UK, that steered her to specialising in gastrointestinal (GI) cancers.
‘Through my SHO training, I found myself drawn to cancer patients and, because I didn’t want to lose the GI aspect [of my training], this was my default,’ she says. ‘I found that I enjoyed GI oncology more than all the other tumour sites, so getting a job fitting with what I liked was the aim.’
Taking up a consultant medical oncologist post at Queen Elizabeth Hospital Birmingham (QEHB) in 2012, Dr Kunene now specialises in upper and lower GI cancers, and cancers of unknown primary. She has taken the lead on multiple clinical trials as principal investigator to continue satisfying her passion for marrying science and clinical practice.
On 31 May 2024, Dr Kunene led a team to administer the very first personalised vaccine against colorectal cancer in England as part of the pioneering NHS Cancer Vaccine Launch Pad (CVLP) initiative.
The overarching aim of this is to speed up access to messenger ribonucleic acid (mRNA) personalised cancer vaccine clinical trials for people who have been diagnosed with cancer to support treatment alongside chemotherapy, as well as prevention.
Speaking at the time of the CVLP launch, NHS chief executive Amanda Pritchard said: ‘Thanks to advances in care and treatment, cancer survival is at an all-time high in this country, but these vaccine trials could one day offer us a way of vaccinating people against their own cancer to help save more lives.’
Working to achieve this ambition is something that Dr Kunene is proud to be a part of, especially as it has the potential for allowing her to offer patients that all-important extra time.
When I started as a registrar 15 years ago, we only used chemotherapy but there were clinical trials in the background where we investigated targeted therapies like trastuzumab (brand name Herceptin) for upper GI cancers. I remember recruiting patients into the ToGA trial and now to see trastuzumab as part of standard of care for HER2-positive upper GI cancers is great.
Of course, we’ve also had the advent of immune checkpoint inhibitors. These immunotherapies are now part of standard of care with or without chemotherapy for patients who have PD-L1 positive or microsatellite-high tumours.
Another treatment combination is chemotherapy with zolbetuximab – an antibody directed against claudin 18.6. Although the QEHB didn’t take part in the related study, our neighbouring hospital of University Hospital Coventry and Warwickshire did, and the results are positive. Zolbetuximab received Medicines and Healthcare products Regulatory Agency approval in August and is currently undergoing review by the National Institute for Health and Care Excellence.
In lower GI cancers, we regularly conduct tests for RAS and BRAF mutations, mismatch repair proteins, NTRK gene fusions and HER2 amplifications. This allows us to utilise appropriate antibodies such as anti-epidermal growth factor inhibitors, immunotherapy, trastuzumab and larotrectinib to positively impact clinical outcomes.
Other drugs like bevacizumab and aflibercept, which are vascular endothelial receptor inhibitors, do not require genomic or immunohistochemistry testing. In suitable cases, these are administered in combination with chemotherapy.
Interestingly, we also see advocacy for old drugs like aspirin, which could improve outcomes in certain groups of patients. Over the years, various study groups have reported improved survival with the use of aspirin and other non-steroidal anti-inflammatories. Thus, it’s not only about new drug discoveries but leveraging current technology to optimise the use of old drugs.
We have witnessed the advancement of radiotherapy with new techniques like stereotactic body radiotherapy, which enables clinicians to deliver high doses of radiotherapy with precision and reduced toxicity. Surgeons are performing more intricate procedures, leading to longer survival for patients due to the increased use of combinations of treatment methods.
We are currently in the era of stratified medicine, where genomic sequencing, circulating tumour DNA, prognostic scoring systems and predictive artificial intelligence models are being optimised so they can be incorporated into routine care to improve survival and reduce treatment toxicity.
The idea of cancer vaccines is not new, but previous studies were not very successful, especially in metastatic settings. Following the Covid-19 pandemic, we have seen increased research into personalised mRNA anticancer vaccines and, so far, early phase studies have shown promising results.
Of course, there are other types of vaccines available such as DNA-based vaccines, peptide-based vaccines and dendritic cell vaccines, which are also being investigated in various tumour groups.
The study that we’re doing is in high-risk, stage two and stage three colon cancers. In these patients, especially the stage three cancers, 20-30% will experience cancer recurrence despite receiving post operative chemotherapy.
For a very long time, we relied on CT scan staging to decide which patients would benefit from chemotherapy, however this method is not reliable.
In the last five to 10 years, there’s been more work in the area of circulating tumour DNA and minimal residual disease in solid cancers. Haematology has always been at the forefront of this, and they have always considered minimal residual disease in their treatments.
We know from recent literature – even just observational studies – that patients who have detectible circulating tumour DNA after the removal of their cancer are at a high risk of cancer reoccurrence. Therefore, this study concentrates on this group of patients.
We offer the patients participation in the study when they attend for consideration of post-operative chemotherapy. If they agree to have both the chemotherapy and the clinical trial, we do screening blood tests for circulating tumour DNA at least four weeks post-surgery, but no later than 10 weeks, as treatment must start within 10 weeks of surgery and not a day later.
Blood tests take a few weeks to become available, so patients continue with their standard post-operative chemotherapy, which could be for three or six months. The results could be either positive or negative for circulating tumour DNA and sometimes the test fails. This is screening phase one.
Screening phase two is for patients who test positive for circulating tumour DNA. If they are happy to continue the study, they will sign a second consent form to allow the study team to manufacture a bespoke vaccine by sequencing the tumour and identifying appropriate neoantigens. A minimum of five and up to 20 neoantigens are required to successfully manufacture the vaccine. These neoantigens are interrogated through a computer algorithm to assess if they can elicit the desired anticancer immune response.
If the neoantigens meet the requirement, the vaccine is then manufactured and can only be given to that particular patient.
What we’re trying to do with the vaccine is re-educate the immune system by generating specific T-cells against the cancer, thus giving the person a fighting chance. Vaccines are normally preventative – we vaccinate against measles, TB, rubella – but these vaccines are not just preventative, they are also therapeutic. If the cancer resurfaces, the immune system should be able to recognise it and get rid of it.
This phase involves blood tests and CT scans at the end of chemotherapy. If the blood results are satisfactory, there is no evidence of cancer recurrence and the vaccine has been successfully manufactured, the patient can be randomised.
Half of the patients will receive the vaccine, and the other half will be observed, which is the standard of care. If a patient is randomised into the vaccine arm, they will receive treatment once a week for the first six weeks, once every two weeks for a month and then every four to six weeks for up to 15 doses over the course of a year.
The vaccine made for the patients who don’t receive it will be destroyed and the ‘blueprint’ used to create the vaccine will not be used for other participants.
Patients who are randomised to standard of care are likely to be disappointed. We warn our patients that they might not get the vaccine. However, we highlight the benefit of receiving much closer monitoring [within the clinical trial] than the usual standard of care protocol.
We conduct blood tests and CT scans more frequently than usual, which increases the chances of detecting cancer recurrence earlier and taking prompt action. We also emphasise that the product is still being studied so we cannot predict the outcome.
The CVLP is a collaboration between NHS England and companies delivering this cancer vaccine technology. The aim is to be able to allow patients across the country to access these vaccine trials. Oxford was the first site to open the CVLP and we received their first patient.
QEHB is one of the vaccine delivery study centres. I also work at Walsall Manor Hospital, a district general hospital, with the CVLP. We [the Walsall team] approach suitable patients based on histology staging. If they agree, we will see them at the QEHB for the circulating tumour DNA screening blood test after signing the consent form. Then, they start chemotherapy at Walsall Manor Hospital, and we inform them of their results as soon as they become available. If they are deemed suitable for the study, they will undergo screening phases two and three if they are still happy to proceed.
One or two hospitals around Birmingham are not part of the CVLP and they also refer patients. Therefore, patients can still access the studies even if their hospitals don’t have the CVLP. We also get a lot of enquiries from colleagues around the country and we can steer them in the right direction.
My colleague Dr Shivan Sivakumar is conducting a vaccine study for pancreatic cancer and I am pleased that QEHB is the first hospital in Europe to have opened the trial. We also have melanoma and lung cancer vaccine studies in our centre run by Dr Lalit Pallan and Professor Gary Middleton, respectively. It would be great to see these studies incorporated into the CVLP. Other hospitals around the country are conducting similar studies in various tumour sites. CVLP is about improving access and delivering the studies to patients with the aim of improving patient outcomes.
When patients hear about CVLP and start to understand the science behind the personalised vaccine, the uptake is relatively high. People want to improve their chances of survival as much as possible, but they also want to take part for the benefit of others. Most of them say: ‘I just want to contribute to the future’.
All these patients have shown a lot of selflessness, saying, ‘even if it doesn’t help me, if it helps somebody else, I’ll be happy to take part in it’. And that’s amazing.
I know there’s a lot of criticism of the NHS and that things could be better in certain areas. I agree. However, some aspects of NHS are beyond the ability of one person or Trust to deliver and we need that coordinated effort to provide something as big as this.
The United Kingdom is doing very well and recruiting faster than other countries. We are really proud of what we are doing. We should build on this model to deliver other research that will only benefit patients.
Dr Victoria Kunene, consultant medical oncologist at Queen Elizabeth Hospital Birmingham, UK, was speaking to pharmacist and medical writer Steve Titmarsh.
21st December 2022
Moderna, in conjunction with Merck, has found that the investigational, personalised cancer vaccine, mRNA-4157/V940, combined with pembrolizumab, was more effective than pembrolizumab alone at reducing the risk of death or recurrence in patients with stage III/IV melanoma following complete resection.
Melanoma of the skin is the 17th most common cancer worldwide with 324,635 new cases and 57,043 deaths in 2020. Although patients diagnosed at Stage 1 have an excellent prognosis, this drops significantly as the disease spreads. For example, regional melanoma (stage 3) has a 63.6% 5-year survival and this drops to 22.5% for those with stage 4 (metastatic) disease.
Pembrolizumab (brand name Keytruda) is a human, programmed death receptor-1 (PD-1) therapy and works to enable T cells to invade melanoma anywhere in the body. The drug is already licensed as monotherapy for the treatment of adults and adolescents aged 12 years and older with advanced (unresectable or metastatic) melanoma.
The KEYNOTE-942 study is an on-going phase 2b randomised study designed to assess whether postoperative adjuvant therapy with mRNA-4157/V940 and pembrolizumab improves recurrence free survival (RFS) compared to pembrolizumab alone in participants with complete resection of cutaneous melanoma and a high risk of recurrence. mRNA-4157/V940 is designed to stimulate an immune response by generating a specific T cell action based on the unique mutational signature of a patient’s tumour.
In the trial, and following complete surgical resection, patients were randomised to receive mRNA-4157/V940 (nine total doses of mRNA-4157) and pembrolizumab 200 mg every three weeks up to 18 cycles (for approximately one year) or pembrolizumab alone. The primary endpoint of the trial was recurrence-free survival whereas secondary endpoints include distant metastasis-free survival and safety.
mRNA-4157/V940 preliminary efficacy data
The results are for 157 patients with stage III/IV melanoma. The data show adjuvant mRNA-4157/V940 and pembrolizumab reduced the risk of recurrence or death by 44% (hazard ratio, HR = 0.56, 95% CI 0.31 – 1.08, one-sided p = 0.0266) compared with pembrolizumab alone.
In terms of safety, serious treatment-related adverse events occurred in 14.4% of patients who received the combination treatment compared to 10% with pembrolizumab alone.
Stéphane Bancel, Moderna’s Chief Executive Officer, said: ‘Today’s results are highly encouraging for the field of cancer treatment. mRNA has been transformative for COVID-19, and now, for the first time ever, we have demonstrated the potential for mRNA to have an impact on outcomes in a randomised clinical trial in melanoma.’
The companies plan to discuss the results with regulatory authorities and initiate a Phase 3 study in melanoma patients in 2023.
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