Messenger RNA vaccines: a new hope against cancer

Dubai, United Arab Emirates - Vita Sarah Bleschner's life changed one Saturday afternoon. She was a middle school librarian, at her home in Oceanside, New York State, when she felt sharp pain in her back.

The acidity medication didn't work to calm the burning feeling, so I went to the emergency department. It was March 7, 2020, just days before New York City hospitals became a war zone due to the coronavirus pandemic.

Doctors subjected Bleschner, then 67, to an ultrasound and CT scan. The result showed that she had a tumor in the pancreas.

I was shocked because she doesn't drink, doesn't smoke, and lives a healthy life. After two days in the hospital, she returned home and began to consider her limited options.

Pancreatic cancer is among the most aggressive types, and one in four patients lives for a year after diagnosis, while only one in ten lives for two years. Feeling the weight of these numbers, Blechner sat down with her husband and three adult children to make calls and search online to decide her next move.

Ultimately, she chose a fast-moving, often misunderstood path in cancer research. Messenger RNA (mRNA) is a single-stranded molecule that transfers genetic information from DNA to direct the formation of proteins.

Most people know it from science lessons at school or from its use in coronavirus vaccines. But long before the emergence of Corona, this field was generating great enthusiasm among cancer researchers.

The German company BioNTech, which designed the Corona vaccine for Pfizer, developed this vaccine based on a platform it had been using to develop cancer treatments for about ten years. Although the "Covid-19" vaccines based on messenger RNA, developed by Pfizer and Moderna, mitigated the impact of the pandemic, they sparked political reactions over the past year, which threatened to slow down or disrupt dozens of potential cancer treatments.

However, after 12 turbulent months, there are signs that this trend is continuing. “It is exciting, as we have seen a number of successes in early trials and positive results,” said Elizabeth Jaffe, deputy director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University.

As for Katherine Wu, a professor at the Dana-Farber Cancer Institute and Harvard Medical School, she pointed out that the recent positive results contributed to the National Cancer Institute announcing assistance to raise $200 million allocated to the development of new cancer vaccines. “We receive significant support from the National Cancer Institute to develop and advance cancer vaccines, and mRNA vaccines are a key part of these efforts,” Wu added.

A cruel enemy To determine her course of treatment, Bleschner turned to doctors at Memorial Sloan Kettering Cancer Center, including Vinod Balachandran, director of the Olayan Cancer Vaccine Center, who said that developing a cancer vaccine is more complex compared to developing a vaccine against a virus or bacteria, because it is connected to the immune system that is prepared to recognize viruses and pathogens as foreign bodies, and therefore the vaccine trains the body to do something that it is already prepared for. Cancer is part of the body itself, and arises from our tissues.”

Most of Balachandran's research over the past two decades has focused on pancreatic tumors, given the difficulty of this disease. “It is a type of cancer for which treatments have not really worked,” he says.

When Bleschner arrived at Memorial Sloan Kettering Cancer Center, Balachandran was starting a trial on an experimental mRNA-based vaccine to treat pancreatic cancer, along with immunotherapy and chemotherapy. He believed that the success of this vaccine might open the door to broader applications, adding: “If we succeed in penetrating the most difficult species, this may help understand how to deal with other species, because it will provide a model on which to build.”

To develop this vaccine, he began by studying what are known as “exceptional survivors,” which are less than 10% of pancreatic cancer patients who live more than five years after diagnosis. It turns out that their immune systems were better able to automatically recognize cancer cells as foreign.

Balachandran explained that these patients have about 12 times more T cells inside their tumors than others, which are a specialized type of immune cell, and these cells may remain in the body for more than a decade in some cases. He also concluded that these cells do not work in general, but rather target specific mutations.

"These T cells were recognizing mutations, but each person's immune system recognizes cancer in a very specific way," he says. "To replicate this, we must teach each individual's immune system how to recognize their own cancer."

That is, we need a vaccine tailored to each patient, and we saw that the best technology to achieve this quickly was to use messenger RNA.” Participation in a research trial After Blechner agreed to participate in the trial, the first step was to perform a surgical procedure known as “Whipple” to remove the tumor from the head of the pancreas.

In a laboratory inside the center, the tumor was preserved and cut into very fine parts, thinner than a human hair. Within less than 72 hours, the sample was sent to Germany, where specialists at Bio-NTech processed it into a clear liquid, a custom vaccine designed specifically for Bleschner.

More than two months after her diagnosis, the vaccine arrived from Germany in New York. At the time, Bleschner had received a dose of immune checkpoint inhibitors, a type of immunotherapy aimed at boosting the ability of immune cells to fight cancer.

During weekly sessions to receive the vaccine, at Memorial Sloan Kettering Cancer Center Hospital in Manhattan, where she remains for about eight hours during which the vaccine flows into her body. After nine weeks, she finished this phase and prepared for the next step: chemotherapy.

But the experiment was very harsh, as she suffered severe side effects that prompted doctors to stop the treatment. She described her condition as follows: “I received only 3 sessions before the treatment stopped, and I was hospitalized and left three or four times.

My weight decreased to about 41 kg, my appetite decreased, I suffered from constant nausea, and my liver was damaged. The doctor told me she didn't expect to see me again."

When she regained some strength, doctors decided that it was no longer safe to resume treatment. She remained hopeful that stopping early would not affect the outcome, but she had to wait to see what would happen.

More than six years later, Bleschner is still alive, doing well, and showing no signs of cancer. Of the 16 patients who participated in Vinod Balachandran's trial, 8 showed a strong immune response to the mRNA-based vaccine.

Of these, 7 were still alive and well six years after the trial began, results presented at the American Association for Cancer Research meeting in San Diego. The implication here is that we may be able to generate a strong immune response against the most difficult types of cancer, and for it to last for a long time.

“If it works here, it could work in many other species.” Although a 16-patient study is inconclusive, a larger multi-site trial began a year ago.

This announcement comes after other positive indicators for pancreatic cancer patients. The New York Times published an interview with former US Senator Ben Sasse from Nebraska, who suffers from advanced pancreatic cancer. He said that he was receiving an experimental drug that shrunk the tumors, despite some painful side effects.

One technology, multiple pathways Sullivan is involved in a number of studies related to mRNA vaccines, including a large trial led by Moderna and Merck that is testing an mRNA-based treatment in parallel with Keytruda, an immunotherapy used to combat melanoma. In January, the two companies announced that this combination reduced the mortality rate among participants by 49% over five years.

A larger phase III trial is currently underway, and the treatment is being tested in other types of cancer, such as non-small cell lung cancer, bladder cancer and renal cell carcinoma. As in the case that helped Pleschner, Merck and Moderna's melanoma treatment relies on a personalized approach, using each patient's tumor cells to tailor a highly precise immune response.

In contrast, another approach relies on what are known as off-the-shelf or generic vaccines, which are not designed specifically for each patient. Bio-NTech and the Moderna-Merck Alliance are developing approaches that use mRNA to encode and deliver a specific set of antigens, i.e. immune targets, often shared by patients with a particular type of tumor, with the aim of stimulating the immune system into a more robust response.

Elias Sayur, a pediatric oncologist and researcher at the University of Florida, is going one step further toward “generalization,” testing mRNA-based vaccines that do not code for any specific antigen at all. In a study published last year in the journal Nature Biomedical Engineering, Sayor treated mice with a “universal” vaccine, which uses mRNA to stimulate the production of a protein called PD-L1, making tumors more likely to respond to immunotherapy.

“We discovered that mRNA does not need to be specific to reprogram the immune response,” Sayor says. “Manufacturing a customized vaccine takes weeks, while the generalization idea aims to activate the immune system more quickly.”

He believes the two approaches could be complementary, as a newly diagnosed patient might receive a generic vaccine to stimulate their immune system, followed later by a tailored vaccine over the course of treatment. The “universal vaccine” approach represents a recent application of this idea, as shown in a study led by Adam Gribben and Stephen Lin of MD Anderson Cancer Center.

The researchers reviewed the records of more than a thousand cancer patients who received immune checkpoint inhibitors and found that receiving the messenger RNA-based Covid-19 vaccine was associated with a significant improvement in response to treatment. The results showed that NSCLC patients who received the Covid vaccine within 100 days of starting treatment lived almost twice as long as those who were not vaccinated.