CAR-T therapy is one of the treatment methods whose creators have a real chance at the Nobel Prize. Several therapies based on this principle have already received official approval from both the US Food and Drug Administration and the European Medicines Agency. CAR-T therapy saves the lives of patients with leukemia, lymphoma and other types of cancer. However, it is only used in patients who have failed all traditional treatments.
The principle of CAR-T therapy is simple. White blood cells from a group of T-lymphocytes are taken from the patient’s blood and these are subjected to an inherited information in the laboratory. After that, T-lymphocytes acquire a special protein, the so-called chimeric antigenic protein (abbreviated CAR). After infusion into the patient’s body, these modified T-lymphocytes bind to the surface of leukemic cells and destroy them.
The healing cells thus eradicate leukemia from the body. The procedure is difficult and expensive. Therapeutic T cells must be prepared separately for each patient. The price is in the hundreds of thousands of dollars. CAR-T therapy for “solid” tumors, such as malignant melanoma or pancreatic tumors, is also under development. But not all problems have been solved there yet.
Researchers led by Jonathan Epstein of the University of Pennsylvania School of Medicine are now coming up with a new modification of CAR-T therapy that takes advantage of mRNA vaccines and targets a serious heart disease called cardiac fibrosis. The study published in the scientific journal Science provides encouraging results for their research on laboratory mice.
Cardiac fibrosis is a very serious threat to patients with heart disease. It is caused by an excessive response of the heart muscle to inflammation or injury, eg after a myocardial infarction. Cells, called fibroblasts, produce excessive amounts of fibrous proteins during fibrosis, and these take away the heart’s elasticity.
A “hardened” heart then cannot perform a full performance. In experiments on mice with cardiac fibrosis, a reduction in the number of fibroblasts in the heart muscle led to a dramatic improvement in health.
“Fibrosis is the root cause of many serious disorders, including heart failure, liver disease and kidney failure, and this technology is proving to be a well-controlled yet affordable way to address this problem,” says Jonathan Epstein. “However, the most remarkable progress is the creation of T-lymphocytes for specific therapeutic purposes without having to remove these cells from the patient’s body.”
The mRNA heals and then disappears
In a 2019 study, Epstein and his colleagues demonstrated that standard CAR-T therapy in mice with cardiac fibrosis can be used to kill hyperactive cardiac fibroblasts and restore cardiac function. However, standard CAR-T therapy would be problematic for the treatment of fibrosis in humans.
Fibroblasts perform important functions in the body, especially in wound healing. CAR T-lymphocytes, which are genetically reprogrammed to attack fibroblasts, could survive in the body for months or even years, depriving fibroblast populations and impairing wound healing.
In a new study, therefore, Epstein and his colleagues proposed a temporary, controllable and at the same time simpler CAR-T therapy. They used technology that has proven itself in the development of mRNA vaccines. They created lipid nanoparticles and encapsulated ribonucleic acid (mRNA) molecules that encode a protein capable of binding in the heart to activated fibroblasts.
The researchers covered the lipid nanoparticles with other molecules that ensure the binding of the nanoparticle to T-lymphocytes. The lipid nanoparticles thus prepared were then injected into mice.
The nanoparticles bound to T-lymphocytes and the mRNA molecules transferred from the nanoparticle to the interior of the white blood cell. They triggered the production of a protein with which the T-lymphocyte gained the ability to bind to fibroblasts. T-lymphocytes then attacked activated fibroblasts and destroyed them. However, this process only lasted for a short time, because the mRNA molecules survive in T-lymphocytes for a maximum of several days.
Then the mRNA disappears and the T-lymphocytes lose their ability to destroy fibroblasts. Although the mRNA lasted only a short time in the mouse body, it still reprogrammed a large population of mouse T cells to kill fibroblasts and the heart fibrosis in the animals subsided. The actual treatment lasted for about a week and then ended spontaneously.
Jonathan Epstein’s team continues to test the entire technology and hopes to soon accumulate enough results to allow researchers from the Food and Drug Administration to receive first phase clinical trials in patients with cardiac fibrosis.
Cover photo: Marco Verch Professional Photographer, CC BY 2.0