A study from researchers in the Perelman School of Medicine at the University of Pennsylvania has shown that an experimental immunotherapy can temporarily reprogramme patients’ immune cells to attack a specific target via only a single injection of mRNA, similar to the mRNA-based Covid-19 vaccines.
The researchers, whose work is published in Science, demonstrated the new approach with an mRNA preparation that reprogrammes T cells—a powerful type of immune cell—to attack heart fibroblast cells. Heart failure is often driven in part by these fibroblast cells, which respond to heart injury and inflammation by chronically overproducing fibrous material that stiffens the heart muscle, impairing heart function—a condition called fibrosis. In experiments in mice that model heart failure, the reduction in cardiac fibroblasts caused by the reprogrammed T cells led to a dramatic reversal of fibrosis.
In the new study, Epstein and colleagues devised a technique for a more temporary and controllable, and procedurally much simpler, type of CAR-T cell therapy. They designed mRNA that encodes a T-cell receptor targeting activated fibroblasts and encapsulated the mRNA within tiny, bubble-like lipid nanoparticles (LNPs) that are themselves covered in molecules that home in on T cells. That technology is also crucial to the mRNA COVID-19 vaccines now in use across the globe.
Injected into mice, the encapsulated mRNA molecules are taken up by T cells and act as templates for the production of the fibroblast-targeting receptor, effectively reprogramming the T cells to attack activated fibroblasts. This reprogramming is very temporary, however. The mRNAs are not integrated into T-cell DNA and survive within T cells for only a few days—after which the T cells revert to normal and no longer target fibroblasts.
The scientists found that, despite this brief duration of activity, injections of the mRNA in mice that model heart failure successfully reprogrammed a large population of mouse T cells, causing a major reduction of heart fibrosis in the animals and a restoration of mostly normal heart size and function with no evidence of continued anti-fibroblast T cell activity one week after treatment.
The researchers are continuing to test this mRNA-based, transient CAR-T cell technology, with the hope of eventually starting clinical trials.
“Fibrosis underlies many serious disorders, including heart failure, liver disease, and kidney failure, and this technology could turn out to be a scalable and affordable way to address an enormous medical burden,” said senior author Jonathan A. Epstein, Chief Scientific Officer for Penn Medicine and Executive Vice Dean and the William Wikoff Smith Professor of Cardiovascular Research in the Perelman School of Medicine. “But the most notable advancement is the ability to engineer T cells for a specific clinical application without having to take them out of the patient’s body.”
“Standard CAR T cell technology involves modifying patients’ T cells outside the body, which is expensive and difficult to scale for common diseases or for use in less wealthy countries,” said study co-author Drew Weissman, the Roberts Family Professor in Vaccine Research at Penn. “Making functional CAR T cells inside the body greatly extends the promise of the mRNA/LNP platform.”
Along with Epstein and Weissman, the other co-corresponding authors are Haig Aghajanian, Co-founder and Vice President of Research at Capstan Therapeutics; and Hamideh Parhiz, PharmD, a research assistant professor of medicine at Penn. Joel Rurik, the lead author, is a PhD candidate in Epstein’s laboratory.