MIT finds way to amplify T-cell response to mRNA cancer vaccines

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Vaccines that turn the body’s immune system against tumors have shown promise in clinical trials, and a handful have been FDA approved for certain cancers. In many patients, however, these vaccines don’t stimulate enough of a response, and the approach some researchers have taken to strengthening it—delivering the vaccine along with immune-stimulating molecules called cytokines—can cause severe side effects.

Now MIT chemical engineer Daniel Anderson and colleagues at MIT, Harvard, and the University of Houston have reported promising results with a different way of attacking the problem: amplifying the T-cell response to mRNA vaccines. The advance could lead to much more powerful cancer vaccines as well as stronger protection against infectious diseases.

Most vaccines generate not only antibodies but also T cells that can activate antigen-­presenting cells, which help tell the immune system what to attack. In their study, the researchers boosted that response with a new type of vaccine adjuvant (a material that can help stimulate the immune system). It consists of mRNA molecules encoding two genes that can switch immune cells into a more active state by turning on certain signaling pathways.

In studies of mice modeling bladder cancer, colon carcinoma, melanoma, metastatic lung cancer, and more, injections of lipid nanoparticles containing the mRNA-­encoded adjuvant enabled the immune system to slow growth of some tumors and eradicate many others. This happened even when the mice were not given a vaccine against a specific cancer antigen, but when they were, the response was stronger still.

“When these adjuvant mRNAs are included in the vaccines, the number of antigen-targeted T cells is substantially increased. These T cells play an important role in the immune response,” Anderson says. The mRNA adjuvant also enhanced the immune response to immunotherapy drugs called checkpoint blockade inhibitors, which work by lifting a brake that tumor cells put on T cells and are FDA approved to treat several kinds of cancer.

“The microenvironment of solid tumors is often hostile to T cells and represents a major barrier to effective immunotherapy. We find that immune remodeling with these adjuvants creates a T-cell-permissive environment and promotes tumor rejection,” says Christopher Garris, an assistant professor at Harvard Medical School and one of the paper’s senior authors.

The researchers also explored whether their adjuvant could boost the immune response to vaccination against viral infection. When they delivered the mRNA particles to mice along with covid or flu vaccines, they found that the vaccine generated a T-cell response 10 to 15 times stronger than usual.

The researchers now plan to test this approach in additional animal models, in hopes of developing it for use in both cancer and infectious diseases.

Meanwhile, they are not the only MIT scientists making exciting advances with adjuvants. A group led by Ana Jaklenec, a principal investigator at the Koch Institute for Integrative Cancer Research, has used one to help the injectable form of the polio vaccine induce a strong mucosal immune response in the GI tract. That could help reduce viral shedding and transmission, a key objective of polio eradication efforts. But to date this immunity has been produced mainly by the oral form of the vaccine, and many countries have stopped using it because it carries rare risks that the injectable version does not.