Nine out of ten people do not survive pancreatic cancer, and survival rates have not improved for nearly 60 years. There are hardly any effective treatment options. So every advance in treatment is a revolution. And that is exactly what is happening now. Researchers in the United States treated 16 pancreatic cancer patients with a personalized mRNA vaccine after their tumors were surgically removed. At 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, excellences are few and far between. In this case, however, pancreatic cancer experts are 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. Gastroenterologist Thomas Sefferlein from Ulm declared it a decisive success with a “completely new approach”. His colleague Alexander Kleger called it a “huge step” that would revolutionize the field.
With only 16 patients, the study published in the journal Nature is small. However, it provides the first evidence of successful use of mRNA technology for one of the most lethal and treatable forms of cancer. It is also a decisive breakthrough in a years-long effort to develop cancer vaccines tailored to individual patients’ tumors.
What was done during the study?
Tumors were removed from patients at Memorial Sloan Kettering Cancer Center in New York and shipped to Germany. The genome of the tumor tissue was then sequenced by the biotechnology company Biotech and examined for the presence of mutations, so-called neoantigens.
A selection of neoantigens to target was then compiled individually for each patient – itself a highly complex process based on years of research – and an mRNA-based vaccine was produced. As with the mRNA vaccine against COVID-19, the goal was to induce an immune response against these neoantigen structures.
Patients were first given the vaccine nine weeks after 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 the 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’m very excited about the fact that there is a clear connection between the induction of immunity and an early signal for longer survival,” said Nina Bhardwaj, who researches cancer immunology at New York’s Icahn School of Medicine at Mount Sinai. Those findings need to be confirmed by larger clinical trials.
Why is pancreatic cancer so deadly?
The pancreas is a small organ located deep in the abdomen. Carcinoma 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 usually have no symptoms until the cancer is abnormally large or has spread to other organs. Although 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. Consequently, no two pancreatic cancers are alike. This makes it especially difficult to treat.
“Each pancreatic cancer is like a disease in itself,” said Alexander Kleger. This makes it “a prime example of a tumor for which you want to generate personalized therapy,” explained Thomas Sefferlein.
Scientists have been surprised by the effectiveness of the vaccine
The idea of fighting cancer with vaccines is not new. A vaccine against prostate cancer has been approved in the US. Back in 2010. And research into mRNA vaccines for cancer has also been going on for some time. Recently, mRNA vaccines developed by Moderna and Merck companies have shown success in treating high-risk melanoma.
Still, many scientists did not expect a vaccine against pancreatic cancer to work. Pancreatic cancer, after all, is classified as a “cold tumor,” meaning it does not elicit a strong immune response and thus hides well from the immune system. Solid tumors usually do not respond to immunotherapy.
“I know they were looking at different types of cancer,” said Drew Weissman, an immunologist at the University of Pennsylvania. “I’m surprised Pancreatic was the one in which it worked so well.”
Cautious optimism—and many unanswered questions
Despite all the initial excitement, some measures of caution are also called for. With only 16 patients, the study had a short 18-month observation period. It was also conducted without a control group, meaning without a comparison group that only received surgery, chemotherapy and checkpoint inhibitors. It is therefore difficult to measure the effectiveness of vaccination alone, and to compare it with previous therapy methods. The fact that each patient received a tailor-made vaccine also makes it difficult to compare study results.
It is still unclear why the vaccine results in an immune response against the cancer in only half of the patients, or how the selection of neoantigens could be optimized in the future. Interestingly, an mRNA vaccine against COVID-19 during the same period elicited an immune response in all patients, indicating that their response to neoantigens was somehow impaired.
It is also unclear whether the vaccine will help patients whose tumors are already so advanced that they are effectively incapacitated. Only patients who could have the tumor removed were included in this study.
“In advanced disease, I think the situation is different,” said Neena Bharadwaj. “There are probably many immune suppressive factors already at play. And even if you generate a good immune response, getting the right cells—in this case T cells—into the tumor itself can be difficult. It’s a big tumor.”
For this reason, vaccination alone may prove to be an inadequate treatment. However, experts emphasize that it can be used as a complementary therapy, for example in the metastatic stage.
Will mRNA vaccines revolutionize cancer treatment?
At this stage, there are also many more practical questions: How much can the process be accelerated? How expensive is the vaccine once established? Ugur Sahin, the biotech’s founder, told the New York Times that over the past few years, the company has been able to reduce production time to less than 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 down the road with lower prices,” said tumor immunologist Niels Halama.
It is also doubtful that the procedure, which experts describe as overly complicated, can be established outside of specialized centers. “This is a vaccine that needs two or three centers in the world right now to be able to do it,” said Drew Weissman. “But ultimately, we want a vaccine that can be used around the world.”
There is still much work to be done, and many unanswered questions. For now, trial and error is the order of the day, according to Drew Weissman. He is convinced that not all cancers respond to RNA vaccines. So maybe it’s not a revolution yet. But this could be the next important step in looking at how we currently treat pancreatic cancer.