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How immunotherapy can be used to treat heart failure



An advanced cancer treatment can also cure certain types of heart failure in mice, researchers reported on Wednesday.

Treatment is a type of immunotherapy called CAR-T, which has been found to be life-changing for some patients with blood cancer. CAR-T relies on engineered white blood cells – T cells – that search for and destroy malignant cells in the body.

In the new study, published in the journal Nature, the technique was used to target scar tissue that solidifies the heart and prevents it from completely relaxing between heart failure patients.

"It's potentially a breakthrough document," Dr. Richard Lee, professor of stem cell and regenerative biology at Harvard who was not involved in the new study.

Medical experts such as Dr. Lee agreed that the study is smart and innovative, and at least a proof of principle. But some asked if it would be possible to use the treatment to treat heart patients, at least in the near future.

For cancer, CAR-T therapy costs about $ 450,000 per patient. When hospital stays are included, the price can increase to $ 1 million or more.

There are six million patients in this country with heart failure; even if the treatment at that price was offered to only a few some of them, the total cost would be astronomical.

Some patients receiving CAR-T therapy experience severe, even fatal, side effects, including very high fever, extremely low blood pressure, and effects on the brain such as confusion or cramps.

Deploying CAR-T against heart failure "is a really smart idea," said Dr. Douglas Mann, professor of medicine at Washington University in St. Louis. Louis. But given the cost of CAR-T and the side effects, he added, it's not practical today.

In heart failure, the walls of the ventricles, the two large pump chambers, solidify and can be enlarged, preventing the heart from pumping blood efficiently through the body. It can be the result of a number of conditions, including heart attack and high blood pressure.

While many patients respond to drug treatment, those with a type called heart failure with preserved ejection fraction have few treatment options. Half die within five years, a mortality comparable to that of some metastatic cancers.

Heart failure is a particular problem for people with muscular dystrophy, Dr. Lee. Heart failure, he said, "is an important life-limiting part of the disease."

Heart muscle solidifies due to scarring, also called fibrosis, Dr. Jonathan Epstein, lead author of the new study and professor of cardiovascular research at the University of Pennsylvania's Perelman School of Medicine.

Fibrosis occurs in a number of other diseases: arthritis, chronic kidney disease and liver cirrhosis, for example. It is the result of the body's response to inflammation. Although fibrosis is responsible for many of the worst symptoms of these diseases, it is not clear what effect the treatment of fibrosis can have.

The idea for the study originated in a postdoctoral student in Dr. Epstein's laboratory, Haig Aghajanian. He wondered: Why can't we do a CAR-T therapy to kill scar tissue in the heart?

He knew how CAR-T works in cancer. The T cells in the immune system constantly scour the body and look for fake cells to attach to and kill. T cells sometimes do not recognize cancer cells, but researchers have found a way to fix it.

They attach a protein to T cells designed to attach to the cancer. When these engineered T cells drift close to a cancer cell, they stick to it and kill it.

As long as because most healthy cells do not have the docking site for the T cell protein, the treatment can work. [19659002] "It's exciting," Dr. Elizabeth McNally, a cardiologist and human geneticist at Northwestern University Feinberg School of Medicine. But, she warned, there are several potential problems for any therapy that attacks fibroblasts.

These are cells that help shape all tissues and they play a major role in wound healing. An ideal treatment should not eliminate fibrosis everywhere, only scars that hinder normal functioning.

To date, Dr. Epstein and his colleagues have not seen problems with wound healing or normal function in their animals, but the work is experimental and preliminary.

Dr. Aghajanian and Dr. Epstein began by placing a docking site on scar tissue cells in the hearts of mice with heart failure. Then they manufactured CAR-T cells that lock into these locations.

Two weeks after the mice were treated, Dr. Aghajanian some pictures to Dr. Epstein. The two sat side by side and looked at them in the microscope. The heart tissue from the untreated mice was filled with scars. The heart tissue from the treated mice was clear.

"It was one of those" aha "moments," Dr. Epstein. "We looked at each other and did a high-five over the microscope."

The next step was to look for a naturally occurring protein found on human fibro cells but not on other cells. The group found one, fibroblast activation protein, or FAP, by looking through a large genetic database.

The researchers found out that mice and other animals also have FAP on scar tissue cells, so they engineered CAR-T cells to search for protein. The treatment worked to clear scar tissue in the mouse heart, and it did not appear to damage other tissue.

Now investigators are beginning to repeat the experiment with dogs.

"I hope we can move to people quickly," Dr. Epstein noted that a group in Germany has found a way to scan the hearts of patients with heart attack and detect FAP.

This would allow physicians to quickly know if patients are candidates for CAR-T.

As for the cost, he thinks it will come down. "First-generation cures are often expensive," Dr. Epstein. But "success and demand drive innovation."

Jeffery D. Molkentin, executive director of the Cardiac Institute at Cincinnati Children's Hospital Medical Center, is also optimistic that the barriers can be overcome.

"It can be transformative," he said.

"The whole idea of ​​constructing T cells to attack cancer is just the tip of the iceberg," he added. "What if we could construct T cells to attack some cells in the body that cause problems?"


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