Scientists create nanoparticle vaccine that prevents cancer

In a breakthrough that could potentially rewrite the prevention and treatment of cancer, scientists have discovered how certain immune cells can break through tumors’ defenses. They have also developed a new nanoscale vaccine that shows promise in preventing cancers from occurring in the first place.

Taken together, the breakthroughs promise a day when the body's own immune system can prevent and fight cancer with greater accuracy and endurance.

Cancer immunotherapy transformed the treatment of most cancers by unleashing the potential of the immune system to kill tumors. Yet, in most patients, the treatments fail because immune cells become exhausted. Tumors naturally adapt to disable or tire out the same cells meant to kill them.

Scientists mapped how CD8⁺ T cells—the body's own killers—are capable of surviving and fighting within solid tumors. By examining the cells at single-cell resolution, the researchers identified a minor subset of tumor-cytotoxic cells. These cells continue to function even in oxygen-starved, nutrient-poor environments in which other immune cells do not.

These hardy T cells employed a second fuel source. Instead of combusting glucose through glycolysis, they switched to oxidative phosphorylation and fatty acid metabolism—an energy strategy that enables them to endure the long term. "We defined a distinctive metabolic signature that permits these cells to escape exhaustion and maintain cytotoxicity," the researchers wrote.

When the researchers boosted these channels of energy in mice, the T cells killed tumor cells better and produced higher levels of interferon-γ, an immune chemical messenger that recruits other immune defenses. The studies showed that metabolic flexibility, not target recognition, foretells how long the immune cells will keep fighting.

Among the populations of tumor-infiltrating T cells that were so diverse, one stood out as extraordinary: a subset of "stem-like" T cells. These cells, characterized by genes TCF1 and LEF1, could self-renew and differentiate into new waves of fighters. If these cells were removed from mouse models, immune attacks collapsed; if they were grown, tumors disappeared and survival increased.

"Stem-like cells are really the engine driver of anti-tumor immunity," the authors of the study concluded. Enabling them, they stated, should be the ultimate goal for the next generation of cancer treatments.

The scientists also discovered that checkpoint inhibitor drugs such as anti-PD-1 therapy—already used in hospitals—work best when they expand these stem-like and metabolically fit T cells. In contrast, people whose immune reactions were regulated by exhausted cells fared badly. When checkpoint therapy was administered with agents that activated mitochondrial function, tumors in mice completely regressed.

The study also found that successful immune responses are dependent on teamwork. Activated T cells clustered next to antigen-presenting cells like dendritic cells in little "immune neighborhoods." Within the pockets, cells exchanged survival signals that kept them alert and active. Dense cancer filled with such neighborhoods was more likely to be sensitive to therapy.

In patients with melanoma, lung, and kidney cancers, in whose tumor samples the researchers found higher levels of these energy-efficient, stem cell-like T cells, the patients lived longer and responded better to treatment. The scientists believe that by measuring the number of these cells, doctors can forecast which patients will benefit most from immunotherapy.

The researchers, employing CRISPR technology, produced T cells that overexpressed the PGC1α gene, which enhances mitochondrial function. When these modified cells were implanted in tumor mice, they survived longer and efficiently killed cancer cells—possessing 2.5-fold the ability to kill compared to normal cells.

This discovery leaves open the door to improving existing therapies like CAR-T cell therapy, which routinely fails against solid tumors. By reprogramming the T cells to better regulate energy, doctors may someday equip them to triumph where cancer usually wins.

While one team worked on making immune responses in cancer stronger, another at the University of Massachusetts Amherst demonstrated another success—stopping cancer from occurring at all.

Biomedical engineer Prabhani Atukorale and her colleagues developed a cancer vaccine based on nanoparticles that shielded mice against melanoma, pancreatic, and triple-negative breast cancer. In one case, it even made the cancers stop their progression to other organs. Up to 88 percent of the immunized mice remained tumor-free.

By engineering these nanoparticles to activate the immune system through multi-pathway activation in combination with cancer-specific antigens, we can suppress tumor growth with very high survival rates," said Atukorale, the study leader.

The vaccine's secret is its design. Traditional vaccines mix an antigen—the antigen that tells the immune system what to target—with an adjuvant, which tells the body it's under threat. But the most effective adjuvants don't mix well together. Atukorale's group solved that by creating a lipid nanoparticle "super adjuvant" that co-stably delivers two immune-stimulating components together in one go, triggering a stronger and more coordinated response.

When mice were immunized with this nanoparticle system and later challenged with melanoma cells, 80 percent of them stayed cancer-free throughout the course of the 250-day study. The control animals did not survive longer than 35 days. The immunized animals also rejected metastasis; none of them developed lung tumors, even when cancer cells were infused around the body.

Atukorale called the phenomenon "memory immunity." Once the body had learned to identify the cancer, it was still ready to fight back should the disease return. "That is a real advantage of immunotherapy, because memory isn't only sustained locally," she said. "We have memory systemically, which is very important.".

Subsequently, the scientists attempted a form developed from tumor lysate—inactive cancer cells from actual tumors—to mimic the complex mixture of proteins in human cancers. The vaccine was shown to protect against a number of different types: 88 percent of mice from pancreatic cancer, 75 percent from breast cancer, and 69 percent from melanoma. The immunized mice did not form metastases when challenged again with the cancer.

"This potent T-cell response is the key to the survival benefit," said Griffin Kane, a postdoctoral fellow and lead author on the paper. "There actually is quite strong immune activation when you treat innate immune cells with this formulation."

The nanoparticle system could be used both therapeutically and preventively. Atukorale and Kane have already begun a company, NanoVax Therapeutics, to commercialize the technology. They hope to be able to design it for people at high risk for specific cancers, for instance, people with very family histories or genetic predispositions.

"The underlying core technology on which our business has been built is this nanoparticle and this treatment approach," said Kane. "The startup allows us to pursue these translational endeavors with the long-term aspiration of making patients' lives better."

They published their study under funding from National Institutes of Health and from the UMass biomedical engineering program and Institute for Applied Life Sciences.

These two studies suggest complementary advances—one boosting the body's native immune warriors and the other preventing cancer from taking up residence in the first place. Discovering how T cells have evolved metabolically could lead to more effective immunotherapies and genetically engineered immune cells that last longer in patients.

Although nanoparticle vaccines could become prophylactic agents for people with extremely high genetic risk, or adjuvant therapy to avoid recurrence after surgery or chemotherapy.

Together, they lead the science of cancer research to an era where prevention and long-term immunity are within reach, if not feasible.

Research findings are available online in the journal Cell Reports Medicine.

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