CAR-T cell therapy, an immune-based therapy that has had notable success in treating difficult cancers, could soon fight one of the most common human ailments—tissue fibrosis (Nature 2019, DOI: 10.1038/s41586-019-1546-z).
Fibrosis occurs when the body tries to fix damaged organs, like what happens in heart disease, kidney disease, cirrhosis, or arthritis. As cells called fibroblasts rebuild withered tissue, what’s laid down is stiffer and less pliable than what existed before, leading to reduced organ function.
Fibrosis is one of the most common outcomes of the most common human diseases, says Jonathan Epstein of the University of Pennsylvania. “There are almost no therapies for fibrotic diseases in the heart or any other organ,” he says, noting a dearth of knowledge about fibroblasts. “It’s just been a big stumbling block in medicine.”
In their new CAR-T fibrosis therapy, Epstein and his team engineered mouse immune cells to find and destroy fibroblasts in the animals through a molecule on the surface of these cells. To do so, the scientists removed T cells from mice and engineered them to express a protein called a chimeric antigen receptor, or CAR, that can recognize FAP, a protein that some fibroblasts express on their surface when they are active and in repair mode. In humans, Epstein says, FAP is one of the most common proteins found in diseased human hearts compared with healthy hearts.
To test the therapy in mice, Epstein’s team gave the animals a form of heart disease by triggering high blood pressure through a drug-hormone combination. They then treated seven of those mice with the engineered T cells. Levels of fibrosis tissue fell from about 7% in diseased hearts to about 2% in treated ones. The treated mice had improved heart function, observed through measurements of blood flow and heart pumping, with as little as 50% of the FAP-expressing fibroblasts destroyed.
That 50% may be enough, Epstein says. While CAR-T cells need to destroy every cancer cell to prevent relapse, it’s ok to leave FAP-expressing fibroblasts behind once the organ’s function has been even partially restored, he says.
To make sure that diseased tissue would still heal after the treatment, the scientists found that, at least in skin, repair still happens in the absence of FAP-containing cells.
Epstein thinks that their treatment will be safe in people. A clinical trial testing a different FAP-targeting CAR-T cell to treat mesothelioma reported no significant side effects. Epstein’s team also designed their FAP-targeting CAR to ward off cytokine storm, a lethal activation of the immune system that hampered early trials of CAR-T for cancer. They engineered the receptor to bind FAP less tightly, squashing some of the T cell signaling that could lead to unfettered cytokine release.
It’s no surprise that people are looking to CAR-T to treat other diseases beyond cancer, says Richard Lee, a heart researcher at the Harvard Stem Cell Institute. But, he says, CAR-T cell therapy is an aggressive treatment, involving removing a person’s T cells, engineering them, and reinfusing them back into the person, and so would be most likely used for serious diseases involving fibrosis, such as some forms of heart failure.
But Lee thinks the new study is clever and clearly innovative. “The team is in good position, given the extraordinary expertise in CAR-T at Penn, to try to turn this into something safe enough to try for patients someday,” he says.
To advance the treatment to humans, Epstein’s team is first performing animal tests on a FAP CAR that would reduce heart fibrosis in muscular dystrophy, a disease much less common than heart disease. This is a regulatory choice, he says, because clinical tests for rare diseases require fewer people and will likely cost less. Proving the effectiveness of using CAR-T to target fibrosis in a rare disease could pave the way for testing it in more common diseases.
“Heart failure is a difficult, and expensive area to do clinical trials, often requiring hundreds and hundreds of patients,” Epstein says.” It would be perhaps quicker to identify more orphan-like diseases to show benefit more quickly.”