Cancer Vaccines Are a 'Marvel'

Vaccines are making waves in the oncology world, with one experimental messenger RNA (mRNA) vaccine, mRNA-4157 (also known as V940), that when combined with the immuno­therapy Keytruda (pembrolizumab), was shown in the KEYNOTE- 942 trial to reduce the risk of melanoma recurrence or death by 44% compared with treatment with Keytruda alone.

Ninety mRNA-based therapeutic cancer vaccines tested in clinical trials since 2000 were listed in findings published in January in Heliyon — with 33 trials having started since 2020 and researchers noting that “the field of mRNA-based drugs is undergoing a rapid transformation, significantly altering the standard of care for numerous diseases.”

mRNA vaccines instruct the body to produce a specific protein that triggers an immune response in a patient’s body, according to the Centers for Disease Control and Prevention. While better known as vaccines to protect from viral infections, mRNA-based vaccines can also have applications in cancer, because mRNA sequences can be made to encode tumor-related protein pieces that can stimulate the immune system against a cancer of interest.

When will such cancer vaccines be approved by the Food and Drug Administration (FDA) and made available to the general public? That remains to be seen.

“It’s going to take years. It’s not going to be available in 2024 or probably even 2025,” says Dr. Jay Berzofsky, chief of the Vaccine Branch of the Center for Cancer Research at the National Cancer Institute. “But, on the other hand, I think if something is really successful, the FDA has ways of fast-tracking approval. So, if there’s a real home run, then it might happen faster than we think, and that would be wonderful.”

Path to the Clinical Trial

Teacher Gary Keblish, 62, of New York City, has lived without recurrence of melanoma for four years since receiving six post-surgical doses of the vaccine-Keytruda combination as part of the KEYNOTE-942 clinical trial at the NYU Langone Health Perlmutter Cancer Center.

The study, findings of which were published in The Lancet, showed that the combination resulted in a recurrence or death rate of 22% at 23 months follow-up, versus 40% at 24 months follow-up among those patients treated with standalone Keytruda.

Keblish’s path to KEYNOTE-942 began in 2019, after a mole on his back burst and began bleeding. His dermatologist sent him to NYU Langone, where, as he says, doctors confirmed that his “cancer was fairly far advanced and had made its way into some lymph nodes beyond the immediate area, and that, too, had to be removed.”

Following surgery for high-risk stage 3C melanoma, he was referred to the trial.

“I think it’s a marvel,” Keblish says of the treatment. “And I would encourage anyone who has the opportunity [to participate in a clinical trial] to do it. As a layperson, in terms of making the decision to do it, my choices were to do nothing further about the cancer that was removed from my body, or to enter a regular treatment plan, a known, established treatment plan, or put my name in the hat, and hope that I can be include in a clinical trial. And it was wonderful to have that choice.”

Researchers reported that the majority of treatment-related side effects were grades 1 or 2 (mild or moderate), with grade 3 (severe) or higher treatment-related side effects occurring in 25% of patients in the combination cohort and 18% of the monotherapy cohort, with no mRNA 4157-related grade 4 or 5 (life-threatening or deadly) side effects.

“The actual injection — because the mRNA vaccine was injected in one arm or the other — left me feeling on some days like I might have felt after getting a regular flu shot, a little swollen and a little sore,” says Keblish. “But [like] on other days or other years when I got the flu vaccine, it was nothing, and there were days or times when I thought, ‘What arm did I get that injection in?’”

While mRNA vaccines achieved public prominence for their use during the COVID-19 pandemic, the platform was already in the works for cancer vaccines, as Berzofsky says.

“In the case of cancer vaccines, there’s been a lot of emphasis in the last couple of years on [working] to target unique antigenic sites that are created by mutations that occur in the DNA just of the tumor cells and not the normal cells, so those [neoantigens, genetically altered proteins present in the tumor] uniquely mark the cancer cells,” Berzofsky says. “… In contrast to chemotherapy, which are mostly sort of poisons that are more toxic to cancer cells than normal cells, but also affect normal cells and that’s why people get so sick from many types of chemotherapy, the immune system can very precisely target just the cancer cells in principle. And one way to do that are these unique mutations that occur only in the tumor cells.”

The difficulty of targeting those mutations, Berzofsky says, is that they’re different in every patient — and so once a mutation is identified, a personalized vaccine has to be made for each patient.

“It basically generates an immune cell response specifically against things that are only in the tumor and not in the normal tissue,” explained Dr. Jeffrey S. Weber, the deputy director of Perlmutter Cancer Center and the senior investigator of the study Keblish participated in. “So, the toxicity should be modest. And in the phase 2 study it was. … It gives the body a chance to mount a specific immune response against those very specific neoantigens. And the [Keytruda] amplifies the response.”

The FDA granted breakthrough therapy designation to the combination for the post-surgical treatment of patients with high-risk melanoma in 2023 based on the results of KEYNOTE-942. Moderna and Merck, the manufacturers of the vaccine and Keytruda, respectively, have initiated V940-001, a phase 3 study evaluating the combination as postsurgical treatment for high-risk stage 2B to 4 melanoma.

Progress Years in the Making

While there have been many cancer vaccine trials in the past, Weber says, they were typically attempts to vaccinate against tumor-associated antigens — substances present in normal tissue but over-expressed in tumors. “Virtually all of those trials failed to show benefit,” Weber says.

Things began to shift in 2017 when a team of researchers led by Dr. Catherine J. Wu of the Dana-Farber Cancer Institute in Boston found that a personalized vaccine targeting patient tumor-specific neoantigens on tumor cells resulted in an anti-tumor response among patients with melanoma.

Further notable progress was made, Weber notes, with 2023 study results from Memorial Sloan Kettering Cancer Center in New York showing that a BioNTech RNA vaccine stimulated T cells in patients with pancreatic cancer.

“In that particular trial, which made a little bit of a splash from [Memorial Sloan Kettering], there were 16 patients treated who had resected [surgically removed] pancreatic cancer, which is, of course, a bad-acting cancer. Half the patients had good immune responses, [and] half didn’t. The half that had good immune responses seem to do better than those who didn’t,” he says.

The accumulated data from a number of small studies, Weber says, led to the study for which he was the lead investigator of 157 patients, including Keblish, with completely resected stage 3B to 4 melanoma, with mRNA-4157 administered for up to nine doses and Keytruda for up to 18 doses in three-week cycles.

Moderna and Merck initially announced in late 2022 that the postsurgical combination reduced the risk of recurrence or death by 44% compared with treatment with Keytruda alone, results reiterated in findings published in The Lancet earlier this year.

The results of KEYNOTE-942 are compelling because, as Dr. Patrick Ott explains, “it’s the first time that these personalized vaccines were tested in a randomized study. … Patients who got the combination vaccine plus the [Keytruda] had a lower recurrence rate. The study was first reported when there was about a year and a half of follow-up [data] for the majority of patients, and now we have an additional year of follow-up and those results have held up, meaning that improved recurrence-free survival has still maintained over time.

“And the main reason why this is exciting is the fact that this is the clearest sign that these vaccines can be likely active, and they can actually prevent a melanoma recurrence from happening in patients,” notes Ott, co-first author on the 2017 personalized vaccine study and director of the Center for Personal Cancer Vaccines, clinical director of the Melanoma Disease Center and director of clinical sciences of the Center for Immuno-Oncology at the Dana-Farber Cancer Institute.

According to the National Cancer Institute, mRNA-4157 is currently being studied in six clinical trials in disease types including renal cell carcinoma and squamous cell carcinoma, as well as melanoma and non-small cell lung cancer.

“There is certainly a lot of excitement about this type of vaccine as preventative or adjuvant treatment,” says Ott, “where patients have a cancer that the surgeon has removed, but they have a sometimes pretty substantial risk for having another recurrence. Let’s say a patient with lung cancer, they had a lung lesion and the surgeon removed it, or the surgeon removed a lymph node from a [patient with] melanoma and then basically, there’s nothing there that the clinician could find on an exam or a radiographic scan.

“Nevertheless, because of the stage of the cancer, we know that a certain proportion of patients will have a recurrence, and so that is where a therapy that could lower that risk for recurrence can help. Adjuvant therapy with the goal of preventing recurrence is a common treatment setting for [patients with] many cancer types. Based on the results from the Moderna study in melanoma patients, many experts currently think that adjuvant [therapy], as opposed to treatment of advanced cancers that cannot be removed by surgery, is the main place of these vaccines.”

Off-the-Shelf Options

In addition to personalized treatments, another class of cancer vaccines — known as off-the-shelf vaccines — are beginning to offer impressive trial results.

“We make the distinction between a customized and an off-the-shelf vaccine,” says Ott. “And it is certainly a lot more cost-, labor- or resource-intensive if one has to generate a new vaccine for every patient, there’s no question about it. It starts with the challenge to obtain an appropriate tumor sample for each patient that actually has enough tumor in it to even provide the basis for starting to make the vaccine, which is not a trivial issue in many patients.”

Time Is Another Factor

“Initial studies routinely took several months to make these personalized vaccines,” Ott says. “Now that time has been shortened to about six to eight weeks. … But nevertheless, it’s still very different if the oncologist who discussed treatment with a patient basically can say, ‘We’ll treat you next Monday, the vaccine is already in pharmacy, let’s go,’ versus ‘OK, well, hopefully we’ll be able to make a vaccine and you’ll start in six weeks.”

One such off-the-shelf vaccine is ELI-002 2P, intended for the postsurgical treatment of KRAS-mutated pancreatic and colorectal cancers. It was shown in phase 1 clinical trial results published this year in Nature Medicine to elicit mutant KRAS-specific T cell responses and tumor biomarker responses in 84% of patients, with a median relapse-free survival (how long a patient lives without signs or symptoms of disease) of 16.33 months, with no dose-limiting toxicities observed.

ELI-002 2P, as explained in a news release issued by The University of Texas MD Anderson Cancer Center in Houston, is a lymph node-targeted vaccine intended to decrease the chance of postsurgical relapse by enabling a patient’s T cells, part of the immune system, to identify and destroy cells with KRAS G12D and G12R mutations.

Samera Rahman, 76, is among the patients who has been treated with ELI-002 2P.

Following more than a month of severe diarrhea in late 2022, an MRI revealed that Rahman had pancreatic cancer. Doctors wanted to administer chemotherapy and then perform surgery, but Rahman insisted on things happening the other way around.

“I said no, that’s not going to happen. I want to do the surgery now,” says Rahman, a real estate broker with homes in California and Maryland. “And I’m so glad for that decision that I was stubborn about and I made because I tell you I didn’t do very well with [postsurgical] chemotherapy. I nearly died each time I got a dose of chemotherapy. I landed in the hospital for a week to 10 days.”

Following surgery, and after ending her course of 12 recommended chemotherapy treatments after four infusions, she enrolled in the AMPLIFY-201 trial at UCLA in Los Angeles, where she starting receiving treatment in August 2023. She now has no signs of disease.

“I had no side effects from the vaccine at all, whatsoever,” she says. “I would get the vaccine in both thighs and both arms once a week initially. And what would happen is it would kind of get like a knot, like a little golf ball [at the injection site], but then it would go away within 24 to 48 hours, it would be gone. I had no other [side] effects. I didn’t have nausea or diarrhea, or any of the other horrible things that I got with the chemo.”

A phase 2 trial is currently underway with a new formulation, ELI-002 7P, designed to target more KRAS mutations.

Rahman has advice and encouragement for anyone considering enrollment in a cancer vaccine clinical trial.

“I felt very fortunate that I got into the vaccine [trial],” she says. “So, what I would say to these people is if you’re able to get into a trial with a vaccine, and they accept you, cooperate with them, do it and consider yourself lucky that you got in.”

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