Wang Lab Publishes Novel Method of mRNA Cancer Vaccination in PNAS

Therapeutic cancer vaccines that train the body’s immune system to recognize and respond to tumor-associated antigens have shown great promise for treating various types of cancer. Now researchers in the Wang Lab at the University of Illinois Urbana-Champaign have reported a novel platform for developing mRNA cancer vaccines. 

“We have developed a new class of mRNA delivery vehicles that do two jobs at once,” said Hua Wang. “They carry tumor-targeting mRNA into dendritic cells and properly activate those dendritic cells so they can better alert T cells to attack cancer. The mRNA vaccine was able to shrink or eradicate multiple types of cancer including lymphoma and breast cancer in mouse models, and provides a promising alternative to existing lipid nanoparticle-based mRNA vaccines.”

During the pandemic, the public became familiar with the power and potential of mRNA vaccines. Though these types of vaccines had been researched in the past, it wasn’t until 2020 that the first one was approved for commercial use in the United States. While this increased interest in mRNA vaccines, researchers have had difficulty expanding their use to other diseases, particularly cancer.

This was the problem that Hua Wang, an associate professor of material science and engineering and bioengineering, set out to solve. His research, led by graduate student Jiadiao “David” Zhou and postdocs Joonsu “Josh” Han and Abhisek Dwivedy, was recently published in the Proceedings of the National Academy of Sciences (PNAS). Their work addresses a core issue with mRNA cancer vaccines: activation of the immune system, specifically dendritic cells. Dendritic cells are the immune system’s “teachers”— they tell the immune system what to target. In order to successfully program these dendritic cells, two things must occur- the mRNA must enter the dendritic cells, and the cell must be activated. Existing systems can deliver mRNA into dendritic cells, but too often fail to activate them quickly enough, if at all.

The team designed an innovative self-adjuvanting α-helical polypeptide, which functioned as both the delivery vehicle for the mRNA and the immune activator. Previous attempts at similar vaccines used separate mechanisms to carry the mRNA and activate the dendritic cells, ultimately limiting their effectiveness. The researchers hoped that by having one molecule perform multiple functions, they could increase the effectiveness of the vaccine.

“The results exceeded our expectations,” said Joonsu. “In a mouse lymphoma model, the platform achieved 83.3% tumor-free survival, a major step forward from previous mRNA cancer vaccines. The vaccine even achieved 33.3% tumor-free survival in 4T1 breast cancer models, a far more difficult environment. Previous mRNA vaccines had 0% tumor-free survival in both settings, demonstrating the efficacy of the team’s model. We also elucidated why the α-helical polypeptides can superiorly activate dendritic cells, i.e., exert a self-adjuvanting effect.” 

David Zhou explained why their compound outperformed other mRNA vaccines. “The success came from addressing multiple bottlenecks at the same time. The α-helical polypeptide stabilizes mRNA, improves uptake into dendritic cells, enhances intracellular delivery and translation, activates dendritic cells, improves antigen presentation and ultimately drives stronger [immune] cell priming.” Zhou also noted the platform did not show notable toxicity, providing a positive sign for this intervention’s safety.

“This work is a product of excellent collaboration and teamwork,” said Wang. “I feel fortunate to have many amazing collaborators on campus, including professors Shuming Nie, Xing Wang, and Joseph Irudayaraj in the Department of Bioengineering, professor Qian Chen in the Department of Materials Science & Engineering, and professor Matthew Berry in the College of Veterinary Medicine.”

The Xing Wang group designed, synthesized and purified the ova and 4T1 neoantigen mRNA for the study. They also performed in silico analysis to provide a mechanistic understanding for the alpha helical peptide's ability to bind and carry mRNA cargoes.

“This is a major step towards the development of mRNA cancer vaccines,” said professor Shuming Nie, co-author and Interim Head of the Department of Bioengineering. “A most innovative feature is that the carrier peptides not only serve to condense mRNAs for delivery, but also act as an adjuvant to activate dendritic cells.”

The team continues to refine the technology, with plans to test the platform in more advanced animal models that better approximate human immune response. Future studies will combine strategies to see what mix will maximize effectiveness against tumors, including checkpoint blockade therapies, cytokine therapies, and cell therapies.

This work was supported by the Air Force Office of Scientific Research (FA9550-23-1-0609), NIH, Sontag Foundation, and American Cancer Society Research Scholar Award.

Grainger Affiliations:

Hua Wang is an associate professor of Materials Science and Engineering and Bioengineering at the University of Illinois Urbana-Champaign. He is also affiliated with the Cancer Center at Illinois, Department of Chemistry, the Materials Research Laboratory, the Beckman Institute for Advanced Science and Technology, and the Carl R. Woese Institute for Genomic Biology.

Shuming Nie is a Grainger Distinguished Chair in Engineering at The Grainger College of Engineering and Interim Head of the Department of Bioengineering. He is affiliated with the Department of Chemistry, the Department of Materials Science and Engineering, and the Department of Electrical and Computer Engineering.

Xing Wang is a professor in the Department of Bioengineering. He is affiliated with the Department of Chemistry, Holonyak Micro & Nanotechnology Laboratory, Carl R. Woese Institute for Genomic Biology, Center for Genomic Diagnostics, and Cancer Center at Illinois.