MIT engineers have developed a new way to amplify the T-cell response to mRNA vaccines — an advance that could lead to much more powerful cancer vaccines and stronger protection against infectious diseases. Most vaccines generate both antibodies and T cells that can target the vaccine antigen by activating antigen-presenting cells, such as dendritic cells. In this study, the researchers boosted the T-cell response with a new type of vaccine adjuvant (a material that can help stimulate the immune system). The new adjuvant consists of mRNA molecules encoding genes that turn on immune signaling pathways and promote a supercharged T-cell response. In studies in mice, this mRNA-encoded adjuvant enabled the immune system to completely eradicate most tumors, either on its own or delivered along with a tumor antigen. The adjuvant also boosted the T-cell response to vaccines against influenza and Covid-19. "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, assisting in the clearance of virally infected cells or, in the case of cancer, killing cancerous cells," says Daniel Anderson, a professor in MIT’s Department of Chemical Engineering. The MIT-MGH team wanted to find a way to make immune responses more powerful. One approach is to deliver immune-stimulating molecules called cytokines along with a vaccine. However, cytokines can overstimulate the immune system, leading to potentially severe side effects. The researchers decided to deliver mRNA strands encoding two genes, IRF8 and NIK, involved in antigen presentation and can switch immune cells into a more active state. The researchers packaged the mRNA in lipid nanoparticles similar to those used to deliver mRNA Covid vaccines, but with a different chemical composition that promotes their delivery to the spleen after being injected intravenously. Inside the spleen, these particles encounter antigen-presenting cells, including dendritic cells. Within 24 hours, these cells begin expressing IRF8 and NIK, helping drive dendritic cells to mature and become activated to prime an anti-tumor response. The researchers tested the immune-remodeling mRNAs in several mouse models of cancer, including aggressive bladder cancer, colon carcinoma, melanoma, and metastatic lung cancer. In nearly all of these mice, the injected mRNA stimulated a strong T-cell response that significantly slowed tumor growth and in many cases completely eradicated the tumors. The mRNA adjuvant also enhanced the immune response to immunotherapy drugs called checkpoint blockade inhibitors. These drugs are FDA-approved for several kinds of cancer but don’t work for all patients. Combining them with the mRNA vaccine adjuvant could offer a way to make them more effective. The researchers also explored whether their new adjuvant could boost the immune response to vaccination against viral infection. When they delivered the mRNA particles along with Covid or flu vaccines, they found that the vaccine generated a 10-to-15-fold stronger T cell response in the mice. The researchers now plan to test this approach in additional animal models, hoping to develop it for use in both cancer and infectious diseases. The research was funded by Sanofi, the National Institutes of Health, the Marble Center for Cancer Nanomedicine, and the Koch Institute Support (core) Grant from the National Cancer Institute.