mRNA Strategy Enhanced T-Cell Responses Across Viral Vaccines and Cancer Models

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,” said Daniel Anderson, professor in MIT’s Department of Chemical Engineering and senior author of the study. “These T cells play an important role in clearing infected or cancerous cells.”

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.” — Riddha Das, co-first author

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.