MIT Turns a Harmless Virus Into a Plug-and-Play Cancer Vaccine, and Finds the Dose of Antigen Matters
Angela Belcher's lab coated an engineered M13 bacteriophage with tumor antigens at controlled densities. In mice, the 35 percent version protected best against melanoma and colon tumors. The work is early and was tested only in animals.
MIT engineers have built a nanoscale vaccine carrier out of a harmless virus and shown that how densely it is coated with cancer antigens changes how well it protects against tumors, at least in mice, according to a study published Friday in the journal Advanced Healthcare Materials and described by MIT News.
The carrier is a modified bacteriophage called M13, a virus that infects bacteria and is harmless to humans. It consists of a single strand of DNA inside a protein shell that forms a long filament, or nanofiber. The researchers attach a cancer antigen, the specific molecule the immune system is meant to target, to one of the shell proteins, called pVIII, by adding the antigen's gene to the virus's DNA.
"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," said Angela Belcher, the James Mason Crafts Professor of Biological Engineering and Materials Science and Engineering and a member of MIT's Koch Institute, who is the study's senior author. Shengnan Huang, a Koch Institute research scientist, is lead author, with graduate students Jack Rudrum, Huaiyao Peng and Hao Nghi Luu.
Belcher's lab has used M13 for more than 20 years, engineering it to self-assemble into scaffolds for 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," she said. "Some of the lessons learned from making batteries and all these other things are now being fine-tuned to make personalized vaccines."
The new step is control over dose. Earlier work in the lab suggested that the density of antigen on the shell affects the strength of the immune response. "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," Huang said. She found she could raise the density of modified pVIII proteins by adding one or two negatively charged amino acids to the protein sequence, and fine-tune it further with a mutation that slows production of the antigen protein.
The team also strengthened the virus's ability to act as its own adjuvant, the ingredient that kick-starts an immune response. Most vaccines need an added adjuvant such as aluminum hydroxide. M13's single-stranded DNA activates an innate immune pathway called TLR9, and the researchers boosted that by changing the viral DNA sequence. "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 results: the researchers made phages displaying a model antigen called SIINFEKL at densities from 6 percent to 70 percent. In mice, they compared a 6 percent and a 35 percent version, and the 35 percent version was most protective. Vaccinated mice were much less likely to develop tumors when later exposed to melanoma cells carrying the antigen and produced more T cells targeting it, in part because dendritic cells were more likely to take up the higher-density particles. In a second experiment, a vaccine carrying ADPGK, a neoantigen found only in tumor cells in a mouse colon cancer model, made mice much less likely to develop colon tumors at the higher density.
The limits matter. This study tested the vaccine as prevention, in mice. The lab's previous work adapted it to treat colon tumors that had already formed in mice, and the team hopes to extend it to other cancers. No human testing is described. Alberto Danielli of the University of Bologna, who was not involved, called it "another cog to improve the translational potential of the M13 phage platform" and said he looks 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."
"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.
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, MIT said.
Open questions: whether the approach works in established tumors at scale, and what it would take to reach human trials.
