New mRNA vaccine strategy dramatically amplifies cancer-fighting T cells

Engineers from the University of Houston, MIT and Harvard have developed a new mRNA-based strategy that dramatically amplifies the T-cell response to vaccines - an advance that could lead to far more powerful cancer vaccines and stronger protection against infectious diseases. 

Unlike conventional vaccine adjuvants, which typically provide short-lived immune stimulation, the new approach reprograms immune cells from within using mRNA instructions that expand cancer-fighting T cells. 

The researchers created the adjuvant using mRNA molecules that deliver instructions for two immune-related genes, IRF8 and NIK, which activate key immune signaling pathways and drive immune cells into a more active state. 

"In studies in mice, this mRNA-encoded adjuvant enabled the immune system to completely eradicate tumors in multiple cancer models, either on its own or delivered along with a tumor antigen," said Presidential Frontier Faculty Fellow Akash Gupta, assistant professor in the William A. Brookshire Department of Chemical and Biomolecular Engineering at UH and a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar, who is the first author of the study published in Nature Biotechnology. "The adjuvant also boosted the T-cell response to vaccines against influenza and Covid-19." 

T cells play a critical role in destroying infected and cancerous cells. The researchers designed the adjuvant to enhance the activity of dendritic cells, which help activate T cells and coordinate immune responses. 

Gupta conducted the research while working as a research scientist at MIT's Koch Institute for Integrative Cancer Research. 

 When these adjuvant mRNAs are included in vaccines, the number of antigen-targeted T cells is substantially increased. These T cells play an important role in clearing infected or cancerous cells." 

Daniel Anderson, professor in MIT's Department of Chemical Engineering and senior author of the study

In mouse studies across several cancer models, the approach generated powerful anti-tumor immune responses and, in many cases, eliminated tumors. These mRNA-based adjuvants also enhanced responses to checkpoint inhibitor therapies and produced a 10- to 15-fold increase in T-cell responses when paired with Covid-19 and influenza vaccines. 

"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," said Riddha Das, co-first author of the paper. 

The researchers now plan to build on these findings by evaluating the platforms in additional models of advanced cancer and clinician-guided translational studies, with the goal of developing new mRNA-based approaches for cancer treatment and infectious disease vaccines. 

The research was funded by Sanofi, the National Institutes of Health, the Marble Center for Cancer Nanomedicine, and the Koch Institute Support Grant from the National Cancer Institute.