番茄社区

At the outset, cancer vaccines were plagued with false starts and modest success at best. But they now represent a promising therapeutic strategy in the immunotherapy of solid tumors.

"You can't read a newspaper today without reading about a cancer vaccine that is doing something," said Mary (Nora) Disis, MD, director of the University of Washington's Cancer Vaccine Institute (CVI) in Seattle. She added that there a few reasons why perceptions are changing about this strategy.

"First, we know the type of immune response we need to eradicate cancer," Disis told 番茄社区. "We need type 1 T cells, and these are both CD8 and CD4 lymphocytes -- the CD4 lymphocytes secrete what are called type 1 cytokines. These are highly inflammatory, and they help the CD8 lymphocytes proliferate and kill. That's not an open-ended question any more -- we need a type 1 T-cell immune response, and that solves a lot of issues in terms of vaccine design."

The second big breakthrough, she said, "is that we know a lot of different immunogens or antigens -- what we need to immunize against."

That's important, she said, "because we are now able to create vaccines that are immunizing against the most important proteins driving a particular kind of cancer -- and that has been somewhat of a game changer."

The next advance is that "we have better technology for delivering vaccines," she said, adding that these include nucleic-based vaccines -- either DNA or RNA -- that stimulate the patients' own immune systems to effectively attack a tumor.

Finally, Disis pointed out that in the past, investigators tended to immunize patients with rapidly growing cancers to try to control cancer growth, "which never made a lot of sense to me."

"Now we're seeing vaccines given in the adjuvant setting, and what the vaccine is trying to do is clear up minimal residual disease and keep the cancer from recurring," she said. "And that's why I think we're seeing so many promising trials in the phase I and II space -- we are trying to put vaccines where they should be, and that's earlier in the disease state."

Emerging Data

CVI is conducting early-stage clinical trials that are targeting a number of solid tumor cancers for vaccine development, including breast, ovarian, colon, lung, bladder, and prostate cancer.

In results from a phase I study in , Disis and colleagues reported that in 66 patients with advanced-stage HER2-positive breast cancer, immunization with a 100-μg dose of a plasmid DNA vaccine encoding the HER2 intracellular domain generated immunity in most patients.

At 10 years after receiving the vaccine, about 75% of the 66 patients were still alive, with about 85% of those patients who received the most immunogenic dose of the vaccine -- 500 μg -- still alive at the 10-year mark, she told 番茄社区.

"Historical rates for that population [suggest] you would expect a median overall survival of less than 3 years at the time the study was started," Disis observed. "Even thought that was a phase I study, it has gained a lot of attention. It was a large phase I study, and it had an interesting clinical outcome."

The vaccine is now being evaluated in a randomized as adjuvant treatment in HER2-low/hormone receptor-negative breast cancer with residual tumor after neoadjuvant therapy. Disis pointed out that CVI also is going to be testing a vaccine for ovarian cancer in a randomized phase II study.

Given the intense activity in cancer vaccine development, regulatory approvals could be expected in the next 5 to 8 years.

There have already been reports of cancer vaccines reducing disease recurrence rates in high-risk melanoma and stage III non-small cell lung cancer (), Disis noted, "and those are going to be advancing to larger clinical trials."

mRNA Cancer Vaccines

The melanoma study Disis referred to was the phase II trial.

Like the mRNA COVID-19 vaccine, mRNA-4157/V940 is based on messenger RNA. It is a personalized cancer vaccine consisting of a single synthetic mRNA coding for up to 34 neoantigens that is designed and produced based on the unique mutational signature of the DNA sequence of the patient's tumor.

Results from that trial in resectable melanoma were presented this year at the American Association for Cancer Research annual meeting by Jeffrey Weber, MD, of the NYU Langone Perlmutter Cancer Center in New York City. The study showed that adding the personalized mRNA cancer vaccine to anti-PD-1 immunotherapy with pembrolizumab (Keytruda) reduced the risk for disease recurrence or death by 44% versus immunotherapy with pembrolizumab alone. showed a 65% reduction in the risk for distant metastasis or death.

The combination beat the single agent in a statistically and "clinically significant" way, Weber told 番茄社区. "It's clear you'd rather be getting the combination of the vaccine with the pembrolizumab rather than the pembrolizumab alone."

While the results were promising, Weber acknowledged some limitations.

"The follow-up is only about 2 years, and the the total number of patients is only 157, and you have to interpret the data with caution," he said. "But the bottom line is that it looks very promising -- promising enough that it will be coming out in Lancet soon, and has provoked a of a 1,000 patients that's already started in Australia, and will start here hopefully in the next month."

"So those are all big deals and, again, all of the other prior neoantigen vaccine studies with peptides, RNA, whatever they were, were all single-arm, small studies, and this is the first randomized study, which is absolutely required to push the field forward," he said.

Moreover, Weber said there is no reason why this approach can't be used with other cancers.

For example, he noted that Merck -- the sponsor of KEYNOTE-942 in collaboration with Moderna -- has "voted with their feet and their wallet" and are pursuing this strategy is NSCLC, hepatocellular cancer, and head and neck cancer -- any cancer that potentially has sensitivity to pembrolizumab.

"That is a large number of cancers," he added. "And I'm sure they are going to do adjuvant studies of vaccine plus pembrolizumab versus pembrolizumab in any, and all, of those histologies."

The safety and efficacy of mRNA vaccines are also currently being explored in multiple ongoing phase I and II clinical trials focused on different types of cancer including melanoma, liver, prostate, and ovarian cancers, as well as other advanced solid tumors.

For example, a study published in Nature earlier this year found that among 16 patients with pancreatic ductal adenocarcinoma, a personalized mRNA vaccine provoked an immune response in half of the patients treated, and those people showed no relapse of their cancer during the course of the study.

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