MIT engineers build nanoscale particles for personalized cancer vaccines

The particle's backbone is a modified, harmless bacteriophage called M13, which forms a nanofiber that can be coated with cancer antigens. By precisely controlling how densely those antigens sit on the fiber, the team found they could shape the strength of the immune response, according to the study published in the journal Advanced Healthcare Materials.

The work extends more than two decades of research in the lab of Angela Belcher, the James Mason Crafts Professor of Biological Engineering and Materials Science and Engineering and a member of the Koch Institute, which previously used M13 phages to build batteries, semiconductors, solar cells and catalysts. "We're taking this toolkit that we've worked on and developed over decades and formatting it to be specific for vaccine therapeutics," Belcher said. Belcher is the senior author of the study; Shengnan Huang, a research scientist at the Koch Institute, is the lead author.

To build a vaccine, the researchers attach an antigen to one of the virus's coat proteins, pVIII. Huang found she could raise the density of these modified proteins by adding one or two negatively charged amino acids to the sequence, and fine-tune it further with a genetic mutation that slows antigen production. The phage can also act as its own adjuvant, because its single-stranded DNA activates the TLR9 innate immune pathway; most vaccines need a separate adjuvant such as aluminum hydroxide. "We can control the exact length. We can control the exact antigen expression, density, pattern, the exact adjuvant amount," Belcher said. "A lot of times with a vaccine, you'll have to put a different adjuvant with it, but now it's all genetically encoded."

The researchers designed phages carrying the model antigen SIINFEKL at densities from 6 percent to 70 percent, then tested two vaccines, one at 6 percent and one at 35 percent; the 35 percent vaccine was the most protective. Mice vaccinated at that density were much less likely to develop tumors when later exposed to melanoma cells expressing SIINFEKL, and generated more T cells targeting the antigen, in part because dendritic cells took up the denser particles more readily.

In a second set of experiments, the team built a vaccine carrying a neoantigen, ADPGK, found only on colon tumor cells in a mouse model of cancer. Mice given the higher-density vaccine were much less likely to develop colon tumors. This study tested the vaccine as a way to prevent cancer; earlier work adapted the platform to treat colon tumors that had already formed. "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 said.

Alberto Danielli, an associate professor of molecular biology at the University of Bologna who was not involved in the study, called the work "another cog to improve the translational potential of the M13 phage platform for cancer immunotherapeutics," and said he looked forward to seeing whether the platform is effective against established tumors and whether additional tumor antigens can be displayed with comparable molecular and immunological efficacy.

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.