A new approach to cancer vaccination yields more powerful T cells

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 and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science.Anderson and Christopher Garris, an assistant professor at Harvard Medical School and Massachusetts General Hospital, are the senior authors of the study, which appears today in Nature Biotechnology. The paper’s lead authors are Akash Gupta, a former Koch Institute research scientist who is now an assistant professor at the University of Houston; Kaelan Reed, an MIT graduate student; and Riddha Das, a research fellow at Harvard Medical School and MGH. Robert Langer, the David H. Koch Institute Professor at MIT, and Ralph Weissleder, a professor of radiology and systems biology at MGH and Harvard Medical School, are also authors.More powerful vaccinesVaccines that stimulate the body’s immune system to attack tumors have shown promise in clinical trials, and a handful have been FDA-approved for certain cancers. In some patients, these vaccines stimulate a strong response, but in others, a weak response fails to kill the cancerous cells.The MIT-MGH team wanted to find a way to make those immune responses more powerful. One way to do that 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.As an alternative approach, the researchers decided to deliver mRNA strands encoding two genes, IRF8 and NIK, which are involved in antigen presentation and can switch immune cells into a more active state.NIK is an enzyme that activates a signaling pathway involved in immunity and inflammation, while IRF8 is a transcription factor that helps program dendritic cells, particularly a subset called cDC1, which are especially effective at activating T cells. These antigen-presenting cells can digest foreign antigens and present them to T cells, stimulating the T cells to mount an immune response against the antigen.“We see that the dendritic cells start shifting toward a more cDC1 phenotype, which is the most important dendritic cell phenotype and can generate a stronger T-cell response,” Gupta says. 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, the particles encounter antigen-presenting cells, including dendritic cells. Within 24 hours, these cells begin expressing IRF8 and NIK, and both of these pathways help drive dendritic cells to mature and become activated so that they can prime an anti-tumor response. Over a few days to a week, the T-cell population expands. These T cells, along with other immune cells such as natural killer (NK) cells, can then recognize and attack tumors.“Most cancer immunotherapies rely on external signals to activate immune cells. We take a different approach — reprogramming immune cells from within by targeting their internal signaling machinery, enabling a more potent and durable anti-tumor response,” Das says. Stronger T cellsThe researchers tested the immune-remodeling mRNAs in several mouse models of cancer, including an 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. This happened even when the mice were not given a vaccine against a specific cancer antigen. When they were, the response was even stronger.“We showed that you can get an anti-cancer response with these adjuvants without including the antigen, just by activating the immune system. However, cancer-specific antigens with the adjuvants in a vaccine further improved the responses,” Anderson says.The mRNA adjuvant also enhanced the immune response to immunotherapy drugs called checkpoint blockade inhibitors. These drugs, which work by lifting a brake that tumor cells put on T cells, are FDA-approved to treat several kinds of cancer. These drugs don’t work for all patients, but combining them with the mRNA vaccine adjuvant could offer a way to make them more effective, the researchers say.“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,” Garris says.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, in hopes of developing it for use in both cancer and infectious diseases. “While there are differences between the mouse systems that we’ve worked in and humans, we are optimistic that these adjuvants will work in humans and could improve a range of different vaccines,” Anderson says.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.