Is There a Future for CAR T-Cell Therapy in Heart Failure?

The promise of chimeric antigen receptor (CAR) T-cell therapy is quickly spreading beyond the cancer space, as evidenced by research published in a recent issue of JAMA on possible new treatments for heart failure.

This group of researchers investigated the use of CAR T cells to repair heart damage caused by cardiac fibrosis, a condition in which fibroblasts—typically helpers in wound healing and maintaining tissue structure—are deposited in excess in the heart, causing it to stiffen. Essentially, this excess “remodels” the heart, the authors say. But few treatments are available to improve symptoms in humans and nothing is approved to reverse the deposits.

CAR T cells are lymphocytes genetically engineered to recognize and bind to specific proteins on cancer cells. That they are chimeric means more than 1 type of tissue is contained in their genetic makeup. Currently, they are used as immunotherapy treatment in various types of leukemia in patients up to age 25 years, who are infused with their own altered cells.

“The use of engineered T cells to treat cancer has revolutionized oncology, and the power of manipulating the immune system is more and more evident in many areas of medicine,” said senior author Jonathan Epstein, MD, of the University of Pennsylvania.

Led by postdoctoral researcher Haig Aghajanian, the group first engineered mouse models with cardiac fibroblasts that expressed a specific peptide. They were then treated with CAR T cells that targeted that peptide, and after 4 weeks, the cardiac fibrosis was significantly reduced compared with the control group.

The second step involved uncovering a protein target for the CAR T cells that the cardiac fibroblasts also expressed. Using gene expression data, the researchers landed on fibroblast activation protein, “a cell surface glycoprotein expressed during embryonic development and active tissue remodeling.”

Again, the cardiac fibrosis was significantly reduced after a month. There was also improvement in heart function.

“The very first experiments were crystal clear, and we knew immediately we were on to something,” Epstein said. “We would like to engineer an even smarter T cell that can be turned on and off to limit any unwanted activities.”

Despite these positive results and FDA approval for use in treating patients with cancer, moving forward with CAR T-cell treatment in the heart failure space remains just a goal for now, with additional safety studies needed in large animal models.

Future researchers will also need to consider that there are instances in which activated fibroblasts protect a damaged heart by providing stabilization, so that if destroyed by T cells, there is a risk of further heart damage.

Reference

Hampton T. Exploring the potential of CAR-T therapy for heart failure. JAMA. 2019;322(21):2066-2067. doi: 10.1001/jama.2019.18942.