MIT engineers create nanoparticles for delivering personalized cancer vaccines

A nanoscale particle with a unique structure, developed at MIT, holds potential as a customizable delivery vehicle for personalized cancer vaccines.

The backbone of the vaccine is a modified, harmless bacteriophage called M13, which forms a nanofiber that can be coated with cancer antigens. By precisely controlling the density of those cancer proteins, the researchers found that they could create a vaccine that prevents the development of colon tumors in mice.

This type of delivery particle could be adapted to carry many different antigens, allowing for the creation of personalized vaccines to treat individual patients’ tumors, the researchers say.

“The great thing about this is that it’s modular and we could switch out different antigens on demand, so you could design it to be patient-specific and target a known antigen for a particular kind of cancer,” says Angela Belcher, the James Mason Crafts Professor of Biological Engineering and Materials Science and Engineering and a member of the Koch Institute.

Belcher is the senior author of the study, which appears today in the journal Advanced Healthcare Materials. Shengnan Huang, research scientist at the Koch Institute, is the paper’s lead author. Jack Rudrum, Huaiyao Peng, and Hao Nghi Luu, graduate students at the Koch Institute, are also authors of the paper.

Viral vaccine assembly

For more than 20 years, Belcher’s lab has been deploying the M13 bacteriophage in a variety of applications. This virus, which is harmless to humans, consists of a single strand of DNA coated in a protein shell, or capsid. 

Belcher has previously developed techniques for generating materials by engineering these viruses to self-assemble into nanoscale scaffolds. By coating these scaffolds with inorganic materials, they can create functional devices such as batteries, semiconductors, solar cells, and catalysts, with precise control over the electronic, optical, and magnetic properties of the materials.

More recently, Belcher’s lab has been developing methods to control features of the phage that could allow it to be repurposed for medical applications, including vaccine delivery. 

“We’re taking this toolkit that we’ve worked on and developed over decades and formatting it to be specific for vaccine therapeutics,” Belcher says. “Some of the lessons learned from making batteries and all these other things are now being fine-tuned to make personalized vaccines.”

The capsid that surrounds the M13 phage forms a long filament made from viral proteins. To create vaccines, the researchers modify one of these proteins, known as pVIII, by attaching an antigen to the end of the protein. This can be done by adding the gene for the antigen to the virus’s DNA.

Some of the lab’s previous work had suggested that changing the density of cancer antigens attached to the capsid could affect the strength of the resulting immune response. In the new study, Huang wanted to find a way to control that density. 

“The antigen is the specific target we want to initiate the immune response against, which means we have to ensure the right dose of antigen to make sure that we can have a strong immune response,” she says.

Huang discovered that she could increase the density of the modified pVIII proteins by adding one or two negatively charged amino acids to the protein sequence. The density could be further fine-tuned by adding a genetic mutation that slows down production of the antigen protein.

In this study, the researchers also figured out how to boost the phage’s own ability to act as a vaccine adjuvant, by changing the genetic sequence of the virus’s DNA. Most vaccines need to be delivered along with an adjuvant such as aluminum hydroxide, which helps to stimulate a strong immune response. However, the M13 phage can act as an adjuvant itself because single-stranded DNA activates a pathway called TLR9, which is part of the body’s innate immune system.

“We can control the exact length. We can control the exact antigen expression, density, pattern, the exact adjuvant amount. A lot of times with a vaccine, you’ll have to put a different adjuvant with it, but now it’s all genetically encoded,” Belcher says. 

Targeting tumors

Using these techniques, the researchers showed that they could design phages that express an antigen called SIINFEKL at densities ranging from 6 percent to 70 percent. SIINFEKL, a small protein that can be engineered into tumors, is often used as a model to test vaccine effectiveness.

The researchers tested two of these vaccines in mice, one with 6 percent density and one with 35 percent, and found that the one with 35 percent was the most protective. 

After vaccination with the higher-density particles, mice were much less likely to develop tumors when later exposed to melanoma cancer cells expressing the SIINFEKL antigen. These mice also generated more T cells targeting SIINFEKL. This is, in part, because dendritic cells, which help to activate T cells, were more likely to take up vaccines with higher antigen density, the researchers found.

In another set of experiments, the researchers created and tested a vaccine carrying a neoantigen, which is only present in the tumor cells. This protein, known as ADPGK, is specifically expressed by colon tumors in a mouse model of cancer. When given the higher density vaccine, these mice were much less likely to develop colon tumors.

In this study, the researchers tested the vaccine as a way to prevent cancer from developing, and in their previous work, they adapted it for use to treat mouse colon tumors that have already formed. In the future, they also hope to use it to combat other types of cancer.

“This interesting work adds another cog to improve the translational potential of the M13 phage platform for cancer immunotherapeutics,” says Alberto Danielli, an associate professor of molecular biology at the University of Bologna, who was not involved in the study. “I look forward to seeing whether this platform is also effective against established tumors and whether additional tumor antigens can be displayed with comparable molecular and immunological efficacy.”

This platform could be especially well-suited for personalized cancer vaccines, because many different antigens could be swapped into the vaccine.

“Because this is a modularly engineered platform, we can change the antigen we are interested in. For colon cancer, we use this specific antigen. For other types of cancer, we can just plug in other antigens and they can be assembled in this platform,” Huang says.

The research was funded, in part, by the Koch Institute Frontier Research Program, the Marble Center for Cancer Nanomedicine, and the U.S. Defense Advanced Research Projects Agency.

Source: MIT engineers create nanoparticles for delivering personalized cancer vaccines