Nine out of ten people do not survive pancreatic cancer, and the survival rate has not improved for almost 60 years. There are hardly any effective treatment options. That’s why every advance in therapy is a revolution. And that is exactly what is happening now. Researchers in the US treated 16 pancreatic cancer patients with a personalized mRNA vaccine after they had their tumors surgically removed. By the end of the 18-month trial period, half of the patients had not relapsed. For a cancer that usually returns within a few months of surgery, that’s a huge success.
In the world of medical science, superlatives are few and far between. In this case, however, pancreatic cancer experts are more than a little excited: Niels Halama, a tumor immunologist at the German Cancer Research Center in Heidelberg, described the latest development as “fantastic” and “unexpected” news. Thomas Seufferlein, a gastroenterologist from Ulm, declared it a decisive breakthrough with a “completely new approach”. His colleague Alexander Kleger called it a “huge step” that will revolutionize the field.
With only 16 patients, the study, published in the journal Nature, is small. However, it provides the first evidence of the successful use of mRNA technology for one of the deadliest and most difficult-to-treat forms of cancer. It’s also a decisive breakthrough in the years-long effort to develop cancer vaccines tailored to the tumors of individual patients.
What was done during the study?
At the Memorial Sloan Kettering Cancer Center in New York, tumors were removed from patients and sent to Germany. The tumor tissue’s genome was then sequenced by the biotechnology company BioNTech and examined for the presence of mutations, so-called neoantigens.
A selection of neoantigens to be targeted was then compiled individually for each patient — itself a highly complex process based on years of research — and an mRNA-based vaccine was produced. Like the mRNA vaccine against COVID-19, the goal was to induce an immune reaction against these neoantigen structures.
This vaccine was administered for the first time nine weeks after the patients went through surgery to remove the primary tumor in the pancreas. In addition, the patients also received chemotherapy and so-called checkpoint inhibitors (these are molecules that prevent cancer from shutting down the immune system).
In the eight patients who showed an immune response, the tumor had not returned by the end of the study. The other eight patients did not show an immune response – they relapsed.
“I am very excited about the fact that there is an apparent correlation between the induction of immunity and the early indication of longer-term survival,” said Nina Bhardwaj, who researches cancer immunology at New York’s Icahn School of Medicine at Mount Sinai, adding that the findings would need to be confirmed by larger clinical trials.
Why is pancreatic cancer so deadly?
The pancreas is a small organ located deep in the abdominal cavity. Carcinoma there is one of the leading causes of cancer death worldwide. The main problem is that pancreatic cancer is usually detected at a very late stage. There is no early detection method, and patients don’t usually have any symptoms until the cancer becomes unusually large or has spread to other organs. Even if it is possible to surgically remove the tumor, it often returns.
Another factor that complicates therapy is that the cancer is constantly changing. It modifies its environment and is itself modified by its environment. s a result, no two pancreatic cancers are alike. This makes it particularly difficult to treat.
“Every pancreatic cancer is like a disease in its own right,” said Alexander Kleger. That makes it a “prime example of a tumor for which you want to generate an individualized therapy,” explained Thomas Seufferlein.
Scientists surprised by vaccine efficacy
The idea of fighting cancer with the help of a vaccine is not new. A vaccine against prostate cancer was approved in the US. back in 2010. And research into mRNA vaccines for cancer has also been going on for some time. Only recently, an mRNA vaccine developed by the companies Moderna and Merck showed success in the treatment of high-risk melanoma.
Still, many scientists did not expect a vaccine against pancreatic cancer to work. Pancreatic cancer, after all, is categorized as “cold tumor,” meaning that it does not elicit a strong immune response and thus hides better from the immune system. Cold tumors usually do not respond to immunotherapy.
“I know they were looking at a bunch of different types of cancer,” said Drew Weissmann, an immunologist at the University of Pennsylvania. “I’m surprised that pancreatic was one that it worked so well in.”
Cautious optimism – and many unanswered questions
Despite all the initial excitement, some measure of caution is also called for. With only 16 patients, the study was as small as the 18-month observation period was short. It was also conducted without a control group, meaning without a comparison group that received only surgery, chemotherapy and checkpoint inhibitor. The effect of vaccination alone is therefore difficult to measure, and a comparison with previous therapy methods is also difficult. The fact that each patient received a tailor-made vaccine also makes it hard to produce a comparative assessment of the study’s results.
It is still unclear why the vaccination resulted in an immune response against cancer in only half the patients, or whether and how the selection of neoantigens can be optimized in the future. Interestingly, an mRNA vaccine against COVID-19 administered during the same period led to an immune response in all patients, indicating their reaction to neoantigens was not impaired in some way.
It is also unclear whether the vaccination helps those patients whose tumors are already so advanced that they are effectively inoperable. The study only included patients who could have their tumors removed.
“In advanced disease, I think the situation is different,” said Nina Bhardwaj. “There are probably many immune suppressive factors already in play. And even if you generate a good immune response, getting the right cells — in this case the T cells — into tumor itself could be difficult. It’s a big bulky tumor.”
For this reason, vaccination alone might prove to be an insufficient treatment. However, experts emphasize that it is conceivable that it could be used as a supplemental therapy, for example at the metastatic stage.
Will mRNA vaccines revolutionize cancer treatment?
At this stage, there are also a great many practical questions: How much can the process be accelerated? How expensive will a vaccine be once it is established? BioNTech founder Ugur Sahin told the New York Times that within the last few years, the company has been able to lower production times to under six weeks, and reduce production costs from $350,000 to $100,000 per treatment. “And with a clinical application on this scale, we can assume that there will be more opportunities with the reduction of the price further on down the road,” said tumor immunologist Niels Halama.
It is also questionable whether the process, which experts describe as highly complex, can be established outside of specialized centers. “This is a vaccine that right now probably requires two or three centers in the world that can do it,” said Drew Weissman. “But ultimately, we’re going to want a vaccine that can be used throughout the world.”
There is still much work to be done, and many unanswered questions remain. For now, trial and error is the order of the day, according to Drew Weissman. He is convinced that not all cancers will respond to an RNA vaccine. So perhaps this is not yet a revolution. But it could well prove to be a crucial next step in overhauling how we currently treat pancreatic cancer.
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