Nanovaccine design boosts immune attack on HPV tumors

Throughout the past decade, Northwestern University scientists have uncovered a striking principle of vaccine design: Performance depends not only on vaccine components but also on vaccine structure.

After proving this concept across multiple studies, the team developed therapeutic cancer vaccines to tackle one of the most challenging targets yet - HPV-driven tumors. In a new study, the scientists discovered that systematically changing the orientation and placement of a single cancer-targeting peptide can lead to formulations that supercharge the immune system's ability to attack tumors.

The study will be published tomorrow (Feb. 11) in the journal Science Advances.

"There are thousands of variables in the large, complex medicines that define vaccines," said Mirkin, who led the study. "The promise of structural nanomedicine is being able to identify from the myriad possibilities the configurations that lead to the greatest efficacy and least toxicity. In other words, we can build better medicines from the bottom up."

Structured success

In conventional approaches to vaccine design, researchers mostly have relied on mixing key components together. Typical cancer immunotherapies, for example, consist of a molecule or molecules from tumor cells (called antigens) paired with a molecule (called an adjuvant) that stimulates the immune system. Physicians mix the antigen and adjuvant together into a cocktail and then inject the mixture into a patient.

Mirkin calls this the "blender approach," in which components are completely unstructured.

Chad A. Mirkin, Northwestern UniversityIf you look at how drugs have evolved over the last few decades, we have gone from well-defined small molecules to more complex but less structured medicines. The COVID-19 vaccines are a beautiful example - no two particles are the same. While very impressive and extremely useful, we can do better, and, to create the most effective cancer vaccines, we will have to."

Mirkin and his team have already applied the "structural nanomedicine" approach to developing SNA vaccines for several different cancers, including melanoma, triple-negative breast cancer, colon cancer, prostate cancer and Merkel cell carcinoma. All have shown promise in pre-clinical models, and seven SNA drugs have already entered human clinical trials for a range of diseases. SNAs also are a part of more than 1,000 commercial products.

Unleashing a stronger immune attack 

In the new study, Mirkin's and Lorch's team turned to cancers caused by HPV, or the human papillomavirus. HPV causes most cervical cancers and a rapidly growing portion of head and neck cancers. While existing HPV vaccines can prevent the viral infection, they do not help patients fight cancer after it has already developed.

To address this gap, the scientists designed multiple therapeutic vaccines that train the immune system's most potent defense - CD8 "killer" T cells - to recognize and destroy HPV-positive cancer cells. Each vaccine particle contains a nanoscale lipid core, immune-activating DNA and a short fragment of an HPV protein already present in tumor cells.

All versions of the vaccine contained the same ingredients. The only difference was the placement and orientation of the HPV-derived peptide fragment, or antigen. The team tested three designs: one that hid the cancer-targeting fragment inside the nanoparticle, and two where it was attached to the particle's surface. In the surface designs, the fragment was attached through its different ends - known as the N terminus and C terminus - a subtle orientation change that can influence how immune cells process it.

Compared to the other versions, the vaccine that displayed the antigen on the particle's surface - attached via its N-terminus - triggered a much stronger immune attack. The killer T cells produced up to eight times more interferon-gamma, a key anti-tumor signal. Those T cells were far more effective at killing HPV-positive cancer cells. In humanized mouse models of HPV-positive cancer, tumor growth slowed significantly. In tumor samples from HPV-positive cancer patients, the vaccine killed more cancer cells by two or threefold.

"This effect did not come from adding new ingredients or increasing the dose," Lorch said. "It came from presenting the same components in a smarter way. The immune system is sensitive to the geometry of molecules. By optimizing how we attach the antigen to the SNA, the immune cells processed it more efficiently."

Transforming 'failed' vaccines by tuning structure

Looking ahead, Mirkin wants to revisit previous vaccines that originally seemed promising but failed to generate sufficiently strong immune responses in patients. By demonstrating that nanoscale architecture drives immune potency, Mirkin's work provides a blueprint for designing more effective therapeutic vaccines for many cancer types based on known components, hastening therapeutic development while lowering its cost.

Mirkin also envisions that artificial intelligence will play a crucial role in the future of vaccine design. Machine-learning algorithms could swiftly comb through the nearly endless combinations of components to pinpoint the most effective structures.

"This approach is poised to change the way we formulate vaccines," Mirkin said. "We may have passed up perfectly acceptable vaccine components because simply because they were in the wrong configurations. We can go back to those and restructure and transform them into potent medicines. The whole concept of structural nanomedicines is a major train roaring down the tracks. We have shown that structure matters - consistently and without exception."

Source:

Northwestern University

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