CAR T cells engineered to target fibroblast activating protein (FAP) could reverse cardiac fibrosis and restore cardiac function in mice, researchers have reported in the Sept. 12, 2019, issue of Nature.
Given the multiple challenges that CAR T cells have had in broadening their success into solid tumors, which are related to both the toxicity and the efficacy end of the spectrum, senior author Jonathan Epstein was surprised, too.
"I thought of this as a long shot when we started," he told BioWorld. "I was definitely surprised at the degree to which fibrosis was ameliorated in the treated animals."
He recalled the first time he and his colleagues looked at tissue slides from treated vs. control animals: "It was obvious [which animals] had been treated and which had not," he said. "You just don't often get a result like that in the laboratory."
Epstein is professor of cardiovascular research at the University of Pennsylvania's Perelman School of Medicine.
He said that in addition to its relevance specifically to heart disease, his team's work is "further evidence that what we like to call the immunorevolution... will advance way beyond cancer."
Not that heart disease and fibrosis aren't big enough problems in their own right. Heart disease is the leading cause of death in both men and women, accounting for about a quarter of all deaths in the U.S.
In some sense, fibrosis is an even bigger problem. According to a recent review article in Science Translational Medicine, it contributes to 45% of deaths globally, playing a role in major killers such as cirrhosis of the liver and rare diseases such as the muscular dystrophies.
"Fibrotic diseases affect almost every organ and tissue," Epstein said, "and yet we have almost no, or no, treatments for them."
To be a viable treatment option in diseases that affect much of the population, the price of CAR T cells will have to tumble. Epstein said that reduced prices are a real possibility, at least from a technology perspective.
"It's important to appreciate how rapidly the field is moving," he said. "I think off-the-shelf-approaches are going to come online soon," which will decrease the cost of making CAR T cells and so could theoretically decrease their price as well.
Given the ubiquity of fibrotic processes – normal scarring and wound healing, too, depend critically on fibrosis – and the penchant of CAR T cells to run amok against their target, the limited off-target toxicity of the intervention described by Epstein and his colleagues is something of a surprise.
Epstein noted that "there were other data using genetic tricks [showing that] you could kill fibroblasts in the heart" without broadly disseminated toxicity.
Additionally, he said, the work illustrates that "there's a lot we don't know about fibroblasts."
For one thing, he said, there are "probably... many different fibroblasts," and they differ in their protein expression profiles.
Previous work has shown, for example, that during normal wound healing, many activated fibroblasts in the skin don't express FAP.
And attempts by other researchers to harness CAR T cells to treat fibrotic lung disease have been less successful than the work now reported by Epstein and his team.
Nevertheless, he acknowledged, "I do think it will be expressed on some activated fibroblasts outside the heart, so that is something people will have to watch out for" in clinical applications. There are existing methods to visualize FAP.
Likewise, "I do worry about having a persistent circulating T cell targeting activated fibroblasts... that might be a problem." His team is working on ways to make the cells temporary through an off switch.
In the long run, though, Epstein expects that a number of fibroblast subtypes will be identified as being potential targets in specific fibrotic diseases.
"Maybe there will be a whole toolkit," he said.
In the near term, the team plans to move to large animal models and explore different diseases to determine which applications would be best suited to taking the work forward into the clinic. One possibility is muscular dystrophy, which, as an orphan disease, offers regulatory advantages. While weakness and wasting are the most striking features of dystrophy, Epstein said that weakening muscles also accumulate scar tissue as they rip under excess strain. For gene therapy approaches to be successful in older individuals, it might be helpful to clear out that buildup of scar tissue.
Heart disease is an umbrella term for many disorders, and which ones the CAR T approach is suited to remains to be seen.
Epstein said that "my expectation would be that would work best for hearts that don't relax well," as is the case in early stages of heart failure. "Once the heart is dilated, then I'm not sure that getting rid of the scar will help."