mRNA delivered by extracellular vesicles induces immunotherapy response in glioblastoma

A group of researchers at The College of Texas MD Anderson Most cancers Middle has developed a brand new methodology for utilizing extracellular vesicles to boost responses to immunotherapy in glioblastoma, doubtlessly opening the door for wider use of engineered messenger RNA (mRNA) for most cancers remedy. The research was printed at this time in Nature Communications.

Earlier this yr, a group of researchers led by Betty Kim, M.D., Ph.D., and Wen Jiang, M.D., Ph.D., developed a novel methodology for loading mRNA into extracellular vesicles, small buildings created by cells to move biomolecules and nucleic acids throughout the physique. The present research builds on that analysis by demonstrating the anti-tumor potential of mRNA-loaded extracellular vesicles.

mRNA therapies, which had been acknowledged by the 2023 Nobel Prize in Physiology or Medication, have lengthy held breakthrough potential in pathogenic infections in addition to ailments like most cancers. Nonetheless, challenges stay to precisely ship mRNA all through the physique. For years, scientists have studied potential supply mechanisms, together with lipid or polymeric nanoparticles, however every of those has its personal limitations.

“There are two major challenges in utilizing mRNA therapies for most cancers remedy. First, how do you precisely goal the tumor cells within the physique? Second, how do you produce sufficient of the remedy for human use?” Jiang stated. “Our strategy solves these two issues.”

The amount downside is solved through the use of a high-throughput system to provide mRNA-loaded extracellular vesicles from engineered cells. Host cells and a designer plasmid encoding the mRNA are subjected to 2 extraordinarily quick electrical pulses, inflicting membranes contained in the cell, in addition to the cell membrane itself, to change into quickly permeable. This leads the cells to secrete many extracellular vesicles loaded with mRNA materials that may then be collected.

For this research, the researchers engineered the extracellular vesicles to specific the CD64 protein on their floor, which serves as a docking mechanism to load each anti-CD71 and anti-PD-L1 antibodies. As soon as within the physique, they search out CD71 and PD-L1, each of that are generally overexpressed in glioblastomas.

These extracellular vesicles had been loaded with mRNA encoding interferon-gamma, an immune signaling protein. When the vesicles bind to receptors on tumor cells, they’re internalized and launch the mRNA.

One motive glioblastoma is troublesome to deal with is that the downregulation of MHC-1, in addition to different options of the tumor microenvironment, create an immunosuppressive atmosphere that evades detection and limits the effectiveness of immunotherapies. The mRNA reverses that, altering the tumor microenvironment to make the tumor detectable to the immune system and extra conscious of immunotherapies. Within the preclinical fashions, a big enhance in survival time and preliminary antitumor exercise was noticed inside 7 days of injection.

“We selected glioblastoma as a result of it has restricted remedy choices at present,” Jiang stated. “We all know that interferon-gamma can induce responses to immunotherapy in glioblastoma, however delivering it to the tumor cells has up to now confirmed to be a serious problem as a consequence of its half-life and the shortcoming for many supply programs to cross the blood-brain barrier. These outcomes hopefully pave the way in which for mRNA-loaded extracellular vesicles for use in most cancers functions.”

In line with Jiang, one of many different benefits of this strategy is that it is plug-and-play, that means it may be tailored to different tumors by merely altering the antibodies to focus on these overexpressed in different tumor varieties.

Additional preclinical work is ongoing to proceed to enhance manufacturing strategies and profile the protection of extracellular vesicles earlier than they’re utilized in medical settings.