Scientists at the University of California (UC), San Diego, have developed an experimental vaccine that could curb the spread of metastatic cancers to the lungs. The key ingredients of the vaccine are nanoparticles that have been engineered to target a protein known to play a central role in cancer growth and spread. The vaccine significantly reduced the spread of metastatic breast and skin cancers to the lungs in mice. It also improved the survival rate in mice with metastatic breast cancer after surgical removal of the primary tumor.

The findings were published in the Proceedings of the National Academy of Sciences in an article titled, “Viral nanoparticle vaccines against S100A9 reduce lung tumor seeding and metastasis.”

“Metastatic cancer accounts for 90% of all cancer-related deaths and continues to be one of the toughest challenges in cancer treatment,” wrote the researchers. “A growing body of data indicates that S100A9, a major regulator of inflammation, plays a central role in cancer progression and metastasis, particularly in the lungs, where S100A9 forms a premetastatic niche. Thus, we developed a vaccine against S100A9 derived from plant viruses and virus-like particles. Using multiple tumor mouse models, we demonstrate the effectiveness of the S100A9 vaccine candidates in preventing tumor seeding within the lungs and outgrowth of metastatic disease.”

A team led by Nicole Steinmetz, PhD, a professor of nanoengineering at the UC San Diego Jacobs School of Engineering, developed a vaccine candidate that can modulate the levels of S100A9 when it goes haywire. When injected subcutaneously, the vaccine stimulated the immune system in mice to produce antibodies against S100A9. The vaccine also increased the expression of immune-stimulating proteins with anti-tumor properties, while decreasing the levels of immune-suppressing proteins.

“S100A9 is known to form what is called a premetastatic niche within the lungs, creating an immunosuppressive environment that allows for tumor seeding and growth,” said study first author Young Hun (Eric) Chung, a UC San Diego bioengineering PhD alumnus from Steinmetz’s lab. “By reducing S100A9 levels, we can effectively counteract the formation of this premetastatic niche, leading to a reduced attraction and increased clearance of cancer cells to the lungs.”

“This is a clever, new approach to vaccination in that we are not targeting tumor cells, but rather the tumor microenvironment so that it prevents the primary tumor from making new tumors,” said Steinmetz, who is also the founding director of the UC San Diego Center for Nano-ImmunoEngineering and co-lead of the university’s Materials Research Science and Engineering Center (MRSEC). “We are essentially changing the whole immune system to be more anti-tumor.”

The vaccine consists of nanoparticles made from a bacterial virus called Q beta. The nanoparticles were grown from E. coli bacteria and isolated. Afterward, a piece of the S100A9 protein was attached to the surface.

“With this form of immunotherapy, we are not necessarily knocking out all of the protein, but we are reducing the levels everywhere,” said Steinmetz.

The vaccine was tested in metastatic mouse models of melanoma and triple-negative breast cancer. Healthy mice were first administered the vaccine, then challenged with either melanoma or triple-negative breast cancer cells through intravenous injection. Vaccinated mice exhibited a significant reduction in lung tumor growth compared to unvaccinated mice. In unvaccinated mice, the injected cancer cells circulated throughout the body and eventually homed in on the lungs to form metastatic tumors.

The researchers noted that this vaccine strategy combats tumor spread, not the primary tumor itself.

“While S100A9 does get overexpressed in certain primary tumors, it is mainly indicated in metastatic disease and progression,” said Chung. “The protein is involved in the formation of immunosuppressive tumor microenvironments. Therefore, we found that our vaccine is much more effective at reducing metastasis, and not in reducing the growth of the primary tumors.”

“These findings are the most clinically relevant, as they closely model what could happen in real-life scenarios,” said Steinmetz. “For instance, a patient diagnosed with an aggressive cancer who undergoes surgery to remove their tumor may be at risk of recurrence and metastasis to the lungs. We envision that this vaccine could be administered post-surgery to prevent such recurrence and outgrowth of metastatic disease.”

Before the vaccine can progress to human trials, more comprehensive safety studies are needed.

“S100A9 is an endogenous protein within the lungs, and there isn’t a lot of data out there that demonstrate what happens when S100A9 is abolished,” said Chung. “We know that S100A9 is important in the clearance of pathogens, and future studies should better test whether reducing S100A9 levels decreases the patient’s ability to fight infections, especially in cancer patients who may have weakened immune systems.”

Future work will also explore the vaccine’s effectiveness when combined with other cancer therapies, with the aim of improving its efficacy against hard-to-treat cancers.

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