A phase 3 clinical trial began for the world’s first “personalised” mRNA vaccine to treat high-risk melanoma in April at University College London Hospitals (UCLH). Since then, further clinical trials using similar technologies have also begun to treat other diseases, including other forms of cancer.
Although mRNA vaccines have been around for many years, they have recently been brought into the spotlight after being administered to billions of people around the world to help fight the Covid-19 pandemic. Building on the promise of the Covid vaccines, research has continued into the use of mRNA vaccines to treat other diseases, for example cancer. Due in part to the many possible mutations and ability to evade the immune system, cancer is extremely difficult to treat. However, mRNA provides the ability to adapt the vaccine to the specific patient and tumour, providing a promising “personalised” approach which could be adapted to treat many types of cancer.
How do mRNA vaccines work?
Traditional mRNA vaccines use a strand of messenger RNA which encodes bacterial or viral proteins, which is then packaged into a delivery vehicle for example a lipid or nanoparticle, and administered to the patient. The mRNA is then taken up and expressed by the patient's cells causing the body to raise an immune response and produce antibodies against the bacterial or viral protein. If the patient is then later infected with the same bacteria or virus, the immune system is prepared to respond quickly before the infection causes serious illness. This technology has been adapted to treat cancer by using mRNA which encodes neoantigens (antigens specific to tumour cells) to prime the immune system to recognise and kill tumour cells.
Promise of a personalised mRNA vaccine to treat melanoma
Unlike previous mRNA vaccines such as the Covid-19 vaccine, which encoded a specific spike protein from the surface of the virus, the personalised vaccine does not deliver mRNA encoding the same protein to each patient. Instead, a sample is first taken of the patient’s tumour and healthy tissue, and the genome of each sample is fully sequenced. Then, an as yet undisclosed algorithm is used to identify mutations specific only to the patient’s tumour, which can then be precisely targeted. The mRNA encoding specific proteins suitable for each patient and their tumour is then delivered using lipid nanoparticles, a widely used delivery method for mRNA and the same method used in some Covid-19 vaccines. Once the vaccine is administered, the mRNA is then translated to introduce tumour-specific targets for the T-cells of the patient’s immune system to attack.
The combination therapy which is the subject of the trial at UCLH is a joint venture between Moderna and Merck Sharp and Dohme. The vaccine uses a combination of a single synthetic mRNA (mRNA-4157 (V940)) with Keytruda (pembrolizumab), a known anti-PD-1 humanized monoclonal antibody used as a checkpoint inhibitor. In the phase 2 trials for treating high-risk melanoma, the combination of mRNA-4157 (V940) and pembrolizumab was shown to reduce the risk of death by 65% in comparison with pembrolizumab alone.
The randomized, double-blind phase 3 clinical trial is being conducted in patients who had received a surgical removal of melanoma in the last 12 weeks. The personalised approach means that if any residual cancer cells are still present after the surgery, or any further cancer cells appear in the future, the patient's immune system is primed to recognise and destroy them, preventing relapse whilst avoiding the patient's own cells.
Intellectual property battles
mRNA vaccines are a highly contentious area in intellectual property, with many ongoing EPO oppositions, appeals and UK court actions. For example, Kilburn & Strode Partner Tom Leonard and Associate Abi Heath recently represented MSD (Merck, Inc.) as one of five opponents who successfully convinced the Board of Appeal to revoke a patent directed to a vaccine comprising an mRNA vaccine and an antagonistic anti-PD-1 antibody, reversing an earlier decision of the EPO to maintain the patent in amended form.
What can we expect next?
The final results of the ongoing UCLH phase 3 trial are not expected until 2029. However, as a result of the promise of the vaccine in phase 2, there are already indications of the possible use of the same “personalised” technology to treat other forms of cancer. In May, another phase 3 clinical trial of a personalised mRNA vaccine was reported, this time co-developed by BioNTech and Genentech to treat bowel cancer.
A further promising phase I trial was also conducted by Genentech, Inc. to treat patients with pancreatic cancer, using the same mRNA technology along with immunotherapy drug atezolizumab (again a PD-L1 inhibitor), to induce a lasting immune response against cancer cells in some patients. This trial has now entered phase 2 trials, which will be completed in 2029.
The future looks positive with respect to the use of personalised mRNA vaccines to treat cancer, mainly due to the ability to edit the mRNA as appropriate in a relatively short time. Currently, it takes 6 weeks from the collection of a sample to the administration of the first mRNA vaccine, although Moderna’s CEO has stated they hope this could be reduced to as little as 30 days. Nevertheless, these vaccines are still subject to the same obstacles which have been plaguing mRNA vaccines for years, for example issues with safe delivery of mRNA into the cells. However, as discussed in our previous articles, there appears to be huge investment into the development of effective delivery methods to facilitate the use of the personalised mRNA technology.
If you have a question relating to this topic, please get in touch with Tom Leonard, Juliette Howarth, Sam Bailey or your usual Kilburn & Strode advisor.