On January 6, the magazine Science published a blockbuster cover article that caused a sensation in the scientific community. The research team from the Perelman School of Medicine at the University of Pennsylvania pioneered the use of mRNA technology to successfully produce T cells in mice for the first time, and repaired the heart function of mice with heart failure through chimeric antigen receptor (CAR) T cell technology therapy.
The study is seen as a milestone, combining the most promising cell therapy today, as well as mRNA biotechnology that "became famous in the first world war" during the COVID-19 pandemic, and is expected to directly prepare T cells in the human body in the future, thereby greatly reducing the high cost of cell therapy.
T cells can be prepared by injecting a needle of mRNA in vivo
The researchers say this experimental immunotherapy allows for transient reprogramming of a patient's immune cells (T cells) to attack specific targets, namely cardiac fibroblasts that cause heart failure, with a single injection of mRNA, similar to giving an mRNA vaccine.
"Fibrosis is the foundation of many serious diseases, including heart failure, liver disease and kidney failure, and this technology could become a scalable and affordable way to address the huge medical burden." Dr. Jonathan Epstein, one of the study authors, executive associate dean of perelman School of Medicine and professor of cardiovascular research at William Wikoff Smith, said.
He stressed that the most significant advance in this research is the ability to design T cells in vivo for specific clinical applications without having to remove them from patients, re-edit and cell culture in vitro, opening up the possibility of large-scale therapies in the future at reasonable cost.
Car-T cell technology is still primarily used to treat cancer, and research developers have long envisioned using this approach for other diseases. A study published by Epstein and colleagues in the journal Nauture in 2019 showed that standard CAR-T cell therapies could be used to attack overactive cardiac fibroblasts in mouse models of heart failure and restore heart function.
Cardiac fibroblasts are produced by the body in response to heart damage and inflammation and have normal and important functions in the body, especially in wound healing. However, if it is overproduced over a long period of time, it will harden the heart muscle and impair heart function, a condition called fibrosis. Fibrosis affects millions of people with heart disease.
So, when targeting heart failure or other fibrotic diseases in humans, the standard CAR-T cell strategy is problematic. Because CAR-T cells that attack fibroblasts can survive in the body for months or even years, thereby inhibiting the number of fibroblasts for a long time and hindering wound healing.
An opinion piece published on the same day in the journal Science argues that extensive clinical experience in the context of cancer treatment suggests that autologous CAR-T cells can last for months or years after adoptive transfer to patients, and that this long-term persistence plays an important role in treatment effectiveness and response persistence. However, heart injuries have different temporal characteristics compared to cancer, and although fibroblast activated proteins (FAPs) are typically lower in healthy tissues, they are upregulated during normal wound healing. Therefore, if a patient is injured after treatment, the long-term presence of FAP-targeted CAR-T cells may pose a safety risk. ’
Gene therapy will eventually become the basis for treatment
In the new study, the researchers addressed the above contradictions. Epstein and colleagues designed an mRNA-based technique that pioneered an instantaneous CAR-T cell therapy with greater procedural simplicity. They engineered mRNA encoding a T cell receptor that targets activated fibroblasts and encapsulates the mRNA in tiny bubble-like lipid nanoparticles (LNPs) that are themselves covered by T cell molecules. The principle of the technique is similar to that of mRNA vaccines currently in large-scale use around the world.
Drew Weissman, co-author of the study and a professor of vaccine research at the Roberts family at the University of Pennsylvania, said: "Manufacturing functional CAR-T cells in vivo greatly expands the clinical application prospects of the mRNA/LNP platform. ”
The scientists found that injecting mRNA in mice simulating heart failure reprogrammed a large number of mouse T cells resulted in a significant reduction in the fibrosis of the animals' hearts and restoring most of their normal heart size and function, with no evidence of sustained antifibroblast T cell activity monitored for a week after treatment.
Heart disease remains the leading cause of death globally and requires therapies that can be mass-produced at a reasonable cost. Researchers are continuing to test this mRNA-based instantaneous CAR-T cell technology and hope to eventually begin clinical trials.
The Science perspective article also states: "These findings provide basic evidence for the use of transient CAR-T cell therapy, and demonstrate the applicability of CAR-T cell therapy beyond oncology applications, providing strong support for the expansion of immunotherapy to disease areas where demand is not met." ”
The head of cardiovascular drug research and development in China of a multinational pharmaceutical giant told the first financial reporter: "The combination of CAR-T and RNA technology, as well as gene editing technology Crispr, etc. will be treated through the concept of chimeric antigen receptor (CAR), which is a field with great potential and many opportunities, of course, including clinical applications other than tumors." But from the perspective of myocardial fibrosis treatment, there is a big difference from animal experiments to humans, and it still needs a long process to achieve. ”
A biomedical investor also told the first financial reporter: "In the future, we will look back many years later and find that CAR-T and other gene editing methods will be the basis for treatment, although today is still far from such a reality." ”