‘This will happen by 2030’: How the science behind the Covid vaccine can help fight cancer | Cancer Research

Men In December 2022, US biotech firm Moderna rose from relative obscurity to prominence during the pandemic. Clinical trial results It made waves in the world of cancer research.

The study, conducted in collaboration with the pharmaceutical company MSD, shows that a messenger RNA (mRNA) cancer vaccine used in combination with immunotherapy will greatly benefit patients with advanced melanoma who have undergone surgery to remove the tumor. has shown that it can lead to After one year of treatment, a Phase IIb study found that the combination reduced the risk of cancer recurrence or death by 44%.

mRNA has become synonymous with Covid-19 vaccines developed by Moderna, Pfizer and BioNTech, but cancer has long been the technology’s ultimate goal. now, NHS launches landmark partnership We are working with BioNTech to accelerate the development of mRNA cancer vaccines over the next seven years.

As part of the partnership, eligible cancer patients in the UK will have early access to clinical trials from autumn 2023 onwards. By 2030, these innovative new treatments are expected to be clinically available for approximately 10,000 cancer patients.

Until recently, the founders of BioNTech, married entrepreneurs Uğur Şahin and Özlem Türeci, were viewed with suspicion by oncologists as providers of technology derided as implausible and unrealistic. Given that, this is a notable development.

“When we first spoke publicly about our approach in 2012, no questions were asked after we spoke,” Shahin says with a laugh. “Then a pharmaceutical executive came to me and said, ‘Very interesting, but this is never going to work. If it works, it’s never going to be affordable.'”

Then came Covid-19. Suddenly, the mRNA was repurposed to create a vaccine against her Sars-CoV-2 virus, which billions of people around the world have since received. Şahin and Türeci became scientific rock stars overnight. new york times And in general, we get the kind of media coverage most executives dream of.

“It’s been a long journey for us,” says Shahin. “Twenty years ago people were asking me, ‘Why are you working on mRNA?’

However, mRNA cancer vaccines are fundamentally different from conventional vaccines such as Covid-19 and HPV vaccines intended to prevent cervical cancer. The focus is not prevention. Instead, they are personalized medicines that train the patient’s immune system to provide the best way to fight their own individual cancer. must be tested and individually tailored to the unique set of DNA mutations causing the patient’s disease.

Moderna and MSD currently plan to initiate a Phase III trial in advanced melanoma in 2023, and BioNTech plans to publish results from its own melanoma trial later this year. Among them, Moderna, BioNTech and CureVac – his third major player in the field – targeting cancer From ovaries to head and neck, colorectal, lungs and even pancreas.

Ultimately, Sahin sees two major niches for mRNA cancer vaccines. The first, combined with CAR T cells or other cell therapies, attempts to shrink large, rapidly growing tumors and prolong the life of patients with advanced disease. There is a risk of death within a few months. The second niche is patients who have recently undergone surgery to remove the tumor to prevent the cancer from recurring or metastasizing.

“As an example of a patient with colorectal cancer, about 30-40% of patients There are recurrences after surgery in the first three years,” he says. “But we can do a circulating tumor DNA test on these patients, which will tell us if there are still cancer cells left after surgery. If positive, those patients will get the vaccine.” .”

However, while there is considerable optimism around the future potential of these vaccines, there are still some major questions to be resolved.

Identifying suitable targets

To create a cancer vaccine, samples of a patient’s tumor and healthy tissue are taken, the DNA and RNA are sequenced, and how these sequences differ between cancer cells and healthy cells. should be compared to identify problematic mutations that can be used as antigens or vaccine targets.

This is where the challenge begins. How do you identify the most relevant mutations that actually cause cancer? This process is known to be easier said than done.

“The genomics of tumor cells is chaotic,” says Cancer Institute professor Alan Melcher. “There are things that are converted to proteins that shouldn’t be converted to proteins, and there are other places where big chunks of DNA are shed, inserted, or turned around. It lacks how to predict the

The researchers believe this ambiguity likely explains some of the variability seen in clinical trials, with some patients experiencing clear benefits from the vaccine in disease settings. Norbert Purdy, an assistant professor at the University of Pennsylvania, has seen trials where the vaccine stimulated the immune system in patients, but said it had little effect on tumors. “I think this is the most important hurdle we have to overcome,” he says. “Why don’t patients always see benefit even when a strong immune response is present?”

When BioNTech and Moderna compare patient tumor cells to healthy cells, they do so by performing genomic sequencing of the small portion of the genome associated with protein production. This would be quicker and cheaper, and their scientists feel that if they can identify aberrant tumor proteins, they should be relatively easy targets for the immune system.

However, as the cost of genome sequencing drops rapidly, World’s first $100 genome was published last year, making whole-genome sequencing more feasible. CureVac is already pioneering this approach, with the aim of potentially identifying subtler and more covert targets related to how the body’s dysfunctional genetics enable tumors to grow.

“Tumor genomes are full of so-called structural variations,” says Ronald Plasterk, Senior Vice President Science and Innovation at CureVac Netherlands. “On average, in lung cancer, there are about 100 to 200 of these structural variants, but they have been completely ignored in previous efforts because the complete genome must be sequenced to elicit them. .”

But while scientists are still working out how best to optimize cancer vaccines against tumors, it may not be long before the first mRNA cancer vaccine hits the market. Moderna and his MSD aim to begin a larger Phase III trial in patients with advanced melanoma this year, and if successful, seek regulatory approval within the next few years. may apply.

The question is whether the NHS can afford it.

Can the NHS buy cancer vaccines?

Personalized medicines such as cancer vaccines are inherently very expensive and complex bespoke products. As a result, UK partnerships with BioNTech are promising, experts say, but much work is still needed to determine if NHS costs are justifiable if clinical trials are successful. .

Christopher Scott, Professor of Cancer Research at Queen’s University Belfast, said this winter’s current crisis highlights how difficult it is for NHS staff to provide the current standard of care without worrying about personalized treatment. It is pointed out that

“We are still not sure if a fully personalized vaccine approach can be offered in the NHS,” says Scott. We have a process, which is great, but it’s still an expensive technology.”

Melcher is more optimistic, but draws parallels with other relatively new cancer treatments such as CAR T-cell therapy. CAR T-cell therapy is available in his NHS, but only for a very limited patient group. CAR T-cell therapies such as tisagenlecleucel – Costs around £282,000 per patient – Extract T cells from a patient’s blood, modify them, and then put them back into the bloodstream. Since 2018, tisagenlecleucel Now available on the NHS Patients with B-cell acute lymphoblastic leukemia under the age of 25 are believed to be the most likely to respond to treatment.

But companies making mRNA cancer vaccines say a number of steps are being taken to make the process of making personalized vaccines as cheap as possible. An electric vehicle manufacturer has developed a small, portable mRNA bioprinter that can be used to automate the process of generating patient mRNA for vaccines.

Şahin concedes that current costs are relatively high, but believes that costs could come down once these vaccines are manufactured for large numbers of patients. “It’s a completely different equation to make a personalized vaccine for 1,000 patients a year than it is to make it for 10,000 or 100,000 patients a year,” he says.

One alternative being explored is a more off-the-shelf form of an mRNA cancer vaccine. A personalized vaccine could help in highly aggressive, rapidly evolving cancers where targeting a highly specific snapshot of the DNA mutations involved is essential, whereas other cancers are at a slower pace. to proceed. In these cases, a standard set of antigens believed to be involved in the disease process in a large number of patients can be used, facilitating mass deployment of vaccines.

There are still many questions that mRNA cancer vaccines will answer. In the years to come, we will have more information about which cancers can be most effectively dealt with – Melcher said that ovarian and pancreatic cancers, due to the nature of their tumors, are better than melanomas. , says it poses a much tougher challenge for cancer vaccines – but we believe it can offer new hope for many people suffering from advanced forms of these diseases.

Shahin is bullish that by the end of the decade, one way or another, patients will have many mRNA cancer vaccines routinely available.

“We believe this will happen on a broader scale by 2030,” he says. “The Covid-19 vaccine and our expertise in developing it have contributed to our work in oncology. I learned how people respond to mRNA.I learned not only about mRNA vaccines and how to deal with them, but also about regulators, so all of this has implications for the development of mRNA-based cancer vaccines. It will help you accelerate.”