When information is transferred from DNA to RNA in cancer cells, errors frequently occur, resulting in the production of proteins that can be recognized by the immune system. For scientists at Arizona State University’s Biodesign Institute, these proteins, known as cancer-specific antigens, are gold, because they believe they can be used to design vaccines that can treat or prevent tumor progression. Now, they have early results from mouse studies that they believe provide proof-of-concept.
The erroneously produced proteins are called frameshift peptides. The Arizona State researchers designed an array of possible frameshift peptides and identified those that are unique to an individual or shared by specific tumor types. From there, they picked vaccine candidates. In studies on mice, the vaccines showed promise in fending off tumors. They reported the results in the journal Scientific Reports.
The study’s senior author, Stephen Johnston, has started a spinout, Calviri, to advance the development of the vaccine technology.
In the past, scientists developing cancer vaccines mostly focused on sequencing DNA from tumor samples. But only 40% of tumors have enough mutations in DNA, while they all make lots of mistakes at the RNA level, Johnston explained in a statement.
Johnston's team used an array to identify almost 400,000 frameshift peptides. Then the researchers screened them against blood samples from both cancer patients and healthy people, looking for those that had the most reactive antibodies.
Of the five different cancer types they examined—lung, breast, brain, gastric and pancreatic—all but glioblastoma had significantly more peptides that reacted to antibodies. That means that in those four cancers, large amounts of frameshift peptides had been released from tumor cells and could be targeted by the immune system.
The majority of the frameshift peptides—69% to 80%—were unique to an individual, while only a small proportion were shared between different samples of the same cancer type, the researchers found. And peptides identified in early-stage cancer were also quite different from those from late-stage cancers, suggesting vaccine constructs should be different for different stages of cancers, the team figured.
Johnston and colleagues then tested the peptides as vaccines in mice. After receiving the vaccines, the rodents were challenged with cancer-causing cells. The researchers found that the vaccines could indeed delay or even prevent tumor growth or progression. What’s more, combinations of multiple peptides produced even stronger results.
Mounting evidence suggests that neoantigens expressed exclusively by cancer cells could be turned into vaccines that train a patient’s own immune system to fight tumors. Scientists at Weill Cornell Medicine recently reported that a vaccine consisting of four neoantigens, when combined with the anti-inflammatory drug naproxen, could extend life in mouse models of Lynch syndrome, a genetic disorder that raises the risk of colorectal cancer.
Neon Therapeutics showed that its neoantigen vaccine could boost the effectiveness of Bristol-Myers Squibb’s immuno-oncology drug Opdivo in patients with lung cancer, bladder cancer and melanoma in a phase 1b study. Earlier this year, Inovio spinout Geneos Therapeutics raised $10.5 million to help advance its own neoantigen projects after its platform showed promise for creating vaccines that stimulate both a CD4+ response and a CD8+ tumor-infiltrating response in animal models.
Based on its current study, Johnston and teammates at Arizona State have made a “top 100” peptide list for each of the five cancers and have just started a five-year study on healthy dogs. If that trial is successful, Johnston’s Calviri plans to create a vaccine candidate for humans, but it would take about 10 years before it's ready for human use, he said.
He remains optimistic about the frameshift peptide approach. These proteins “are much more immunogenic than the point mutations used in personal cancer vaccines,” he said in the statement. “Most importantly, we can make off-the-shelf vaccines for therapeutic or even preventative vaccines which will be much less expensive."