mRNA technology enables CAR-T-cell therapy in the patient’s body

Treatment of cardiac fibrosis

© CAR-T-cell therapy using mrNAJonathan A. Epstein et. – University of Pennsylvania (UPenn)

Robert Klatt

The mRNA technology enables CAR T cell therapy directly in the patient’s body. Previously, T cells had to be taken from the blood, genetically modified in the laboratory and then used again in the body. In the future, cardiac fibrosis and other diseases could be treated better.

Philadelphia (USA). Medicine has been using CAR-T-cell therapy for a few years to treat certain leukemia and lymphomas. To do this, T cells of the immune system are taken from the patient’s blood and then genetically modified in the laboratory so that their surfaces carry the chimeric antigen receptor (CAR). The CAR-T cells are then transfused back into the patient’s body. There they find and eliminate cancer cells with the help of the receptor. This is usually done after chemotherapy to kill any remaining cancer cells.

In principle, CAR-T-cell therapy can also be used to treat other diseases such as cardiac fibrosis, an indicator of cardiac insufficiency. “Heart failure is the most common referral diagnosis for inpatient treatment in Germany,” explains immunocardiologist Florian Leuschner from Heidelberg University Hospital. Heart fibrosis can be triggered by many diseases, including high blood pressure, heart valve defects and heart attacks.

Treatment of cardiac fibrosis using CAR-T-cell therapy

In cardiac fibrosis, fibroblasts (connective tissue cells) try to replace injured heart cells. However, due to excessive fibroblast activation, this can lead to stiffening of the organ. So far this cannot be dealt with.

CAR-T cell therapy can attack the activated fibroblasts and thus prevent cardiac fibrosis. However, the method has major disadvantages. In addition to the high effort involved in the removal, modification and transfusion of the CAR-T cells, it is primarily the fact that they remain in the body for a long time that is critical. The genetically engineered CAR-T cells attack target cells for several months to years. This is intended in cancer medicine to switch off tumor cells, but not in the case of fibroblasts, which are necessary for wound healing.

CAR-T cells by mRNA technology

Scientist the University of Pennsylvania (UPenn) have in the trade magazine Science A study has now been published that demonstrates a possibility of treating cardiac fibrosis using CAR-T-cell therapy. The CAR-T cells were formed directly in the body of the test animals using mRNA technology.

This is possible because the mRNA technology brings the blueprint for the desired receptor directly to the T cells. These then form the desired CAR T cells in the body. Because the mRNA is short-lived, the effect only occurs for a short time. Wound healing is therefore not hindered in the long term.

Experiments with mice

To demonstrate the feasibility of the new treatment method, Jonathan Epstein’s team carried out experiments with mice. As part of the study, the animals with cardiac insufficiency were injected with mRNA containing the blueprint for the protein FAP (fibroplast activation protein). The protein also activates fibroblasts in humans.

As with the Covid-19 vaccine, the mRNA was packaged in lipid nanoparticles. In addition, it was linked to antibodies so that it can reach the T cells of the immune system directly. The T cells with the FAP receptor were then able to recognize and deactivate fibroblasts.

Restoration of cardiac function

After just 48 hours, the intravenous injection actually led to the reprogramming of many T cells. Cardiac fibrosis improved in the mice after about two weeks. This was shown by the fact that the function and size of the organ had returned to normal. In the spinal cord of the animals, no more T cells that are directed against fibroblasts could be found just one week after the infection. This confirms the short life of the mRNA.

Clinical studies in a few years

“Modified mRNA therapies are likely to have wide-ranging applications,” the scientists state. According to them, the formation of modified T cells by means of mRNA in the patient’s body is suitable for the treatment of various diseases because the short life of the CAR T cells limits side effects.

Before the procedure can be used clinically, according to Florian Leuschner, various questions still need to be clarified. In addition to the optimal dosage strategy, this also includes checking the general tolerance. In addition, it must be ruled out that excessive immune reactions occur. The expert estimates that clinical studies with humans will begin in about five years. However, Leuschner is already of the opinion that mRNA methods can be used safely in the future for the treatment of cardiovascular diseases.

Can also be used for other diseases

According to the head of the study, Epstein, the procedure can also be used for other diseases. “Many serious diseases are fibrosis based, including heart failure, liver disease, and kidney failure. This technology could prove to be a customizable and affordable way to address a huge medical burden, ”explains the researcher.

Science, doi: 10.1126/science.abm0594


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