As mRNA vaccines have been pushed into the spotlight thanks to the pandemic, researchers are using this as a base to design personalised treatments for patients to train their own immune system to fight cancer.
The messenger RNA (mRNA)-based COVID-19 vaccines, developed by BioNTech and Moderna in under a year, changed the course of the pandemic.
Yet the technology has been progressing for more than 20 years. Before COVID-19, researchers were diligently working with mRNA to find a therapeutic vaccine for cancer. With this new-found pandemic fame came a renewed vigour for the whole field, reports Pharmaceutical Journal.
“The pandemic led to an unprecedented increase of investment into this technology,” says Ulrike Gnad-Vogt, senior vice-president and area head (oncology) at CureVac, an mRNA biotech company in Tübingen, Germany, “not only validating the approach scientifically but enabling significant growth due to funding, which was just not there before.”
Early work
mRNA vaccines work by carrying instructions that tell the body’s cells to make particular proteins. These are then recognised by the immune system as foreign, and antibodies are produced. Once the proteins are made, the mRNA degrades. If this degradation did not happen, then proteins would be produced in perpetuity. This fragility is why, initially, mRNA was seen as too difficult to work with.
Despite this perceived instability, using mRNA remained a tantalising prospect for some cancer vaccine researchers. Kim Lyerly, professor of surgery, pathology and immunology, was working in the late 1990s at Duke University, Durham, North Carolina, where he collaborated with fellow faculty and cancer immunologist Eli Gilboa, making vaccines with dendritic cells, which show antigens to the surface of T-cells to train the immune system to recognise and destroy them.
The researchers took genetically identical mice with identical tumours and immunised the mice using mRNA in dendritic cells. They saw that the mice’s immune system became educated against the tumour, ultimately destroying it. The crucial step, Lyerly says, was getting the mRNA into the dendritic cells early, so that it remained stable.
“Naked mRNA is often degraded rapidly by ribonoclease (RNase) enzymes. Getting it into cells allows it be translated into proteins, which are more stable,” says Lyerly.
Simultaneously, Vrije Universiteit Brussel (VUB) researchers were examining dendritic cells as part of cancer vaccines. This led to the development of an mRNA-based adjuvant whereby, in addition to tumour-associated antigens, dendritic cells contain three mRNAs that encode for three immune-stimulating proteins. Once in the body, these dendritic cells can migrate to the lymph nodes and activate the T-cell response.
With this research growing stronger, commercialisation was an obvious next step.
Commercialisation
CureVac, founded in 2000, was the first company to develop and run clinical studies with mRNA vaccine technology, initially targeting cancer but progressing to other disease areas.
Then, in 2008, BioNTech, based in Mainz, Germany, was founded to to specifically develop personalised cancer therapies based on mRNA. Two years later came Moderna, and several other mRNA start-ups, including eTheRNA in Belgium, born from the work at VUB.
Unlike vaccines for cervical cancer, where a virus underlies the disease, mRNA vaccines are used as a therapy, teaching the body how to fight the cancer once it is present.
Two main strategies are used to develop mRNA cancer vaccines. First, a generalised vaccine whereby researchers find proteins are common to a group of cancers and develop mRNA to make those proteins, similar to the work at VUB; second, a highly personalised vaccine whereby individual tumours are sequenced to develop vaccines based on proteins specific to each person’s cancer, called neo-antigens.
Some progress is being made in making a generalised cancer vaccine.
Karine Breckpot, head of the Laboratory for Molecular and Cellular Therapy at VUB, has shown in various mouse cancer models that the mRNA-based adjuvant can render tumours into an autovaccine without further addition of antigen mRNA. This removes the need to search for the best target neo-antigens, she says.
Nevertheless, personalised vaccine technology is further ahead for now.
For any of the mRNA vaccines to work, the mRNA must be combined into a deliverable format – usually, by encapsulating it in a lipid nanoparticle. At low pH, these tiny particles carry a positive charge, allowing genetic material to form a complex inside the lipid shell. Once in the body, the pH changes and the particles become neutral, allowing them to deliver their cargo safely.
Tandem attack
Once the mRNA vaccines have successfully made it into the body, they can be used with other therapies to trigger a strong immune response, the most promising being immune checkpoint inhibitors. Checkpoint proteins can stop the body’s immune system from responding to cancer cells, so inactivating these with checkpoint inhibitors allows the immune system to continue fighting the tumour.
This combination of therapies is essential in the fight against ever-moving targets, like mutating cancer cells, agrees CureVac’s Gnad-Vogt.
“Cancers have developed mechanisms to escape from immune attack and, even if a cancer vaccine induces immune responses, there is no guarantee it will control tumour growth. Combination with other treatment modalities, like checkpoint inhibitors, is key, at least in patients with advanced cancer, but this makes the clinical development also more complex.”
And, even when the vaccines use personalised neo-antigens, results have been mixed, says Breckpot. “For certain patients, it’s beneficial, for others, it does nothing. We need a better understanding of why some benefit from this type of vaccine while others don’t.”
Manufacturing
With mRNA established as a workable technology, attention has turned to the vaccine manufacturing process. An advantage of mRNA vaccines is they are easier to make than conventional vaccines, which have historically taken 10-15 years to develop and use disabled forms of bacteria, viruses or protein molecules.
Conventional vaccines are manufactured in cell cultures and require large factories: the manufacturing process for mRNA vaccines is cell-free and avoids the need to grow highly pathogenic organisms on a large scale.
The pipeline
Given the speed with which the COVID-19 vaccines made it into clinics, why have cancer vaccines stalled?
“Unlike SARS-CoV-2, which affects humans similarly, cancer in each individual is unique, necessitating a more personalised approach,” says Praveen Aanur, vice-president and therapeutic area head (oncology) at Moderna.
So each tumour must be sequenced to identify the relevant peptides before the mRNA can be made.
“The development of personalised mRNA-based therapeutics to treat diseases like cancer is a frontier only at the beginning of its potential,” says Aanur, but the work on COVID-19 vaccines will benefit the development of cancer vaccines.
Moderna, CureVac and BioNTech have several cancer vaccines in their pipelines in association with various pharmaceutical companies and positive results are starting to filter through.
Trial evolution
Another consequence of the pandemic that could benefit the development of mRNA cancer vaccines is the speed at which the COVID-19 vaccines whipped through clinical trials.
“How we do clinical trials has been changed forever,” says Sam Godfrey, research information team leader at Cancer Research UK. “COVID-19, particularly, led to some of the fastest clinical process progress we’ve ever seen. Now we’re seeing smaller, faster, more agile trials, which also brings the cost down.”
And, as a signal of the increased investability of mRNA cancer vaccine technology, in May, CureVac announced a partnership with bioinformatics-based immunotherapy business, myNeo, to escalate its antigen-identifying process. The next month, CureVac acquired Frame Cancer Therapeutics, which specialises in antigen discovery technology. Combining this technology with CureVac’s general vaccine technology could create a panel of neo-antigens that could be used across many more patients.
The timescales for getting a cancer mRNA vaccine to the clinic are predictable. But Moderna hopes to have an update on its proof-of-concept personalised cancer programme later in 2022.
Meanwhile, CureVac’s Gnad-Vogt says that, as well as the vaccines currently under evaluation, the company hopes to enter phase I trials with a second-generation technology in 2022. This technology, already used to make an updated COVID-19 vaccine in collaboration with GSK, optimises the nucleotide sequence of the mRNA to make proteins for a longer period, triggering a stronger immune response, among a few other tweaks.
mRNA vaccines are only going to get more exposure. For those who have been in the field for 30 years, the success of the COVID-19 vaccines is a pivotal part of the story. Lyerly says: “Twenty years ago, people said, ‘This is a stupid idea. Why would anybody do this?’ And now it’s, ‘This seems like such a good idea. Let’s do it’.”
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