Customizing mRNA vaccines for cancer

In the future, treating some cancer cases might look a lot like going to the doctor for a flu shot. Just as flu vaccines train the immune system to recognize and fight off influenza viruses, cancer vaccines train the immune system to mount a strong attack against a growing tumor in the body.

"Cancer vaccines have always been a long sought-after goal and have been tried over the decades by the whole scientific community, mostly built on this knowledge that vaccines have essentially been the most impactful medicine in all of human history to improve health,” said Vinod Balachandran, a cancer surgeon and researcher at Memorial Sloan Kettering Cancer Center.

A scientist in a white coat stands smiling in a laboratory.

Vinod Balachandran and his colleagues at Memorial Sloan Kettering Cancer Center investigate the use of precision mRNA cancer vaccines to treat pancreatic cancer.

Credit: Memorial Sloan Kettering Cancer Center

Today, cancer vaccines are finally becoming a reality, thanks to work from Balachandran and others. Their newfound success comes from an mRNA approach that tailors the vaccine to an individual’s cancer. In this case, the mRNA encodes for neoantigens — proteins that exist only in tumors — that trigger an individual’s immune system to launch an attack. Researchers can now customize and deliver personalized mRNA cancer vaccines to a patient within about six weeks.

“The ability to do this with mRNA, which can make whatever target, theoretically, that you want into a fast vaccine, this really is powerful for the community,” said Balachandran. His team recently published promising results of a Phase 1 trial using precision mRNA cancer vaccines to treat patients with one of the most fatal cancers, pancreatic cancer, which takes the lives of nearly 90 percent of its patients (1,2).

With encouraging results in hand, many cancer researchers are optimistic that cancer treatment will be revolutionized by simple injections of mRNA molecules. At the same time, they are solving mRNA delivery challenges and refining the artificial intelligence algorithms that identify the best neoantigens to target in each person.

Personalizing pancreatic cancer treatment

When Balachandran and his colleagues first began working in this area, pancreatic cancer was considered one of the least suitable targets for a cancer vaccine. “The prevailing thinking at the time had been that pancreas cancers, since they have very few mutations, they would not generate these [neo]antigens,” said Balachandran.

With no neoantigens to target, scientists could not develop a cancer vaccine. But after studying the rare 10 percent of patients with pancreatic cancer who survive the disease, Balachandran’s team found that their immune systems could successfully mount strong responses targeting mutation-derived neoantigens in their tumors (3). With that data in hand, they reasoned that an mRNA vaccine that prompts the immune system to target these neoantigens might provide the ideal boost needed to treat pancreatic cancer for all patients.

The most exciting part is having the patients come back to clinic time after time after time, and [they’re] not recurring and doing well,
– Jeffrey Weber, New York University Langone Health

Around the same time, Balachandran’s group began discussions with BioNTech and Genentech to develop customized mRNA cancer vaccines. This partnership led to a small Phase 1 clinical trial with 16 patients who were given an intravenous precision mRNA cancer vaccine in combination with an immune checkpoint inhibitor and chemotherapy drugs.

In May 2023, the researchers reported that of the 16 patients, half showed evidence of strong immune responses targeting the neoantigens within their unique tumors (1). Specifically, the mRNA vaccine activated neoantigen-specific T cells that kill tumor cells. In patients exhibiting these strong immune responses, the cancer did not recur for the entire 18 months of the study. However, cancer did recur in patients who did not show strong immune responses activated by the vaccine.

“The strength of the immune response was definitely very notable,” said Balachandran. However, he cautioned that with such a small Phase 1 trial, they cannot prove that the mRNA cancer vaccine caused the improvement in relapse rates. That question will be answered in their randomized Phase 2 clinical trial that is currently recruiting around the world.

The Phase 2 clinical trial will also seek to determine why half of the patients did not generate a strong immune response to the mRNA vaccine. Balachandran hypothesizes that this might relate to spleen removal as part of pancreatic cancer treatment for some patients. Because the mRNA cancer vaccine was given intravenously, it relies on lymphoid organs like the spleen to generate a response.

With more research, precision mRNA cancer vaccines may offer a breakthrough for pancreatic cancer, a disease with a low survival rate that has remained largely unchanged for nearly 60 years (4).

Mounting durable immune responses

Precision mRNA cancer vaccines may also be effective for treating cold tumors, which are hard-to-treat cancers that don’t respond to immunotherapies (5). In a Phase 1 clinical trial of 14 patients with cold tumors of different cancer types, researchers led by Karin Jooss, a vaccine developer at Gritstone bio, showed that a precision mRNA cancer vaccine, in combination with two immune checkpoint inhibitors, was safe and led to activation of T cells specific to the individual’s neoantigens (6).

A photograph of a smiling woman with brown hair and a pink button-down shirt.

At Gritstone bio, Karin Jooss leads a team of scientists studying precision cancer vaccines with self-amplifying mRNA that allows for smaller doses.

Credit: Nancy Rothstein Photography

This trial tested self-amplifying mRNA, which rapidly replicates the target neoantigen after injection. “What we learned in this first-in-human study is for self-amplifying mRNA, because of its potency, less is better,” said Jooss.

Because the study was carried out during the COVID-19 pandemic, the study team also serendipitously learned about their impressively durable responses. The researchers had scheduled monthly intramuscular mRNA injections, but due to many patients missing appointments during the pandemic, some patients received injections every 12 weeks instead. “At that point, sometimes after three months, the T cells were higher than three months before,” said Jooss. “The durability is something I had never seen in nonhuman primates or in patients.”

The use of precision mRNA cancer vaccines may also add benefits for cancers that already respond well to immunotherapies. At the 2023 American Association for Cancer Research meeting, Jeffrey Weber, an oncologist at New York University Langone Health, in collaboration with Moderna and Merck, showed that combining a precision mRNA cancer vaccine with an immune checkpoint inhibitor in patients with high-risk melanoma decreased the risk of recurrence or death compared to patients taking the immune checkpoint inhibitor alone (7). The added benefit of the mRNA cancer vaccine over and above the traditional immune checkpoint inhibitor therapy suggests that a combination therapy may prove essential for patients with melanoma.

“The most exciting part is having the patients come back to clinic time after time after time, and [they’re] not recurring and doing well,” said Weber. “That's when you realize you’ve got something that's going to work.” The Phase 3 trial is currently in progress, and the FDA granted the vaccine a Breakthrough Therapy Designation to help move it along quickly. “We'll continue to understand when you mount a good immune response why it works. And if you don’t, why it doesn't work,” said Weber.

Unanswered questions

According to Weber, the next frontier for precision mRNA cancer vaccines will be figuring out which neoantigens are the best ones to target in each individual. Answering that question will require more work on the artificial intelligence side of mRNA cancer vaccines, in which researchers are training algorithms to identify the optimal target neoantigens for each person. “[We] need information from wet lab experiments to feed back into these algorithms, because it's artificial intelligence. And the more information you give, the better this artificial intelligence becomes. It's a self-learning system,” said Karine Breckpot, a cancer immunology researcher at Vrije Universiteit Brussel.

A photograph of a man with gray hair and glasses wearing a red necktie.

Jeffrey Weber is a medical oncologist at New York University Langone Health studying the use of precision mRNA cancer vaccines to treat patients with melanoma.

Credit: Jeffrey Weber

As research continues, other approaches to individualized cancer vaccines may also show success. Another common approach uses peptides, which are protein fragments that mimic the antigen of interest to trigger an immune response (8). But mRNA researchers believe that the mRNA approach has several advantages over peptides. Jooss, who has worked with peptides in preclinical models, said that the immune responses appear to be more short-lived than responses to mRNA. And Weber pointed out that unlike mRNA vaccines, where scientists can inject dozens of mRNA molecules encoding for different neoantigens, it’s only possible to inject a few peptides at a time due to volume constraints within the injection. That’s because peptides are much less soluble than mRNA, so they require much higher concentrations.

“The future belongs to the RNA vaccine approach,” said Weber. But not everyone is as certain. “[The mRNA vaccines are] cheaper; they're faster to produce; you can put many more antigens in mRNA. So, it's great. But do we completely forget about peptide vaccines? Do we forget about DNA vaccines? … I would say no,” said Lana Kandalaft, a cancer vaccine developer at the Ludwig Institute for Cancer Research. “The results will speak for themselves.”

To personalize or not to personalize

Another topic of debate within the field of precision mRNA cancer vaccines is whether the personalized factor is necessary or not. Depending on the type of cancer, there may be neoantigens that are shared across people that could be used in a one-size-fits all mRNA cancer vaccine (9).

Gritstone bio is one of the companies currently testing both personalized and nonpersonalized mRNA vaccine approaches. For nonpersonalized vaccines, Jooss said that it’s preferable to deliver multiple epitopes that are present in each patient’s tumor. “This multi-epitope match between the cancer and the vaccine, we believe is important to actually provide durable benefit so that the tumor cannot as easily escape the immune pressure,” said Jooss.

A nonpersonalized approach would certainly be easier for companies to manufacture the vaccines more quickly. But Weber believes that it will be well worth the extra time because the immune responses will likely be stronger for individualized neoantigens that are specific to someone’s unique tumor. “My personal feeling is it will take a personalized approach to truly be effective,” he said.

The future of mRNA cancer vaccines

Regardless of the nature of the approach, researchers in the field are also addressing other challenges related to packaging the mRNA. Currently, the use of lipid nanoparticles to encase the mRNA within a fatty protective barrier is common. But Breckpot noted that these lipid nanoparticles can activate the immune system in ways that might not always be beneficial to fighting cancer. “If we know perfectly well what the lipids are doing, and they have an acceptable immune activation that does the job that we want, fine. But if we find out the lipid nanoparticles are activating pathways that maybe are not well fit in the context of cancer, then it might be better to use something neutral,” said Breckpot. She added that it may be possible to use polymers or other materials that are hidden from the immune system.

The future belongs to the RNA vaccine approach.
– Jeffrey Weber, New York University Langone Health

According to Balachandran, it will be important to look for additional technologies that might allow the mRNA cancer vaccine to be given in fewer injections. In their trial for pancreatic cancer, the study design required nine doses total.

The efficacy of precision mRNA cancer vaccines to fight a variety of cancers will come into much sharper focus over the next five to ten years. Just as the most recent trials included immunotherapies, mRNA cancer vaccines likely will not be used alone. Activating T cell responses to recognize the neoantigen and attack the tumor is one thing, but cancer tumors still have ways to suppress the T cells. “It will not be enough,” said Breckpot. “I would love to see the opposite. But I truly think that we will still need to modulate the tumor microenvironment so that the T cells can exert a full functionality.”

The need for combination therapies doesn’t diminish Weber’s view of the potential for mRNA cancer vaccines. “It will change the way we treat our patients. … Slowly but surely, we're going to close in on curing the majority of patients,” he said. “[To quote] Frank Sinatra, the best is yet to come.”