CAR T cells produced in vivo may treat cardiac injury

By Monish Makena, The Science Advisory Board contributing writer

January 13, 2022 -- New evidence suggests that immunotherapy could have the potential to temporarily reprogram patients' immune cells to attack a specific target via a single injection of mRNA. The study, published in Science, could lead to a new treatment for heart failure.

Heart failure is often driven in part by fibroblast cells. These cells respond to heart injury and inflammation by chronically overproducing fibrous material that stiffens the heart muscle, thus impairing heart function, a condition called fibrosis.

Clinical trials using antifibrotic therapeutics have only demonstrated a modest effect. To address this clinical challenge, researchers at the University of Pennsylvania (UPenn) have demonstrated the use of CAR T cells to specifically eliminate activated fibroblasts as a therapy for heart failure. (Science, January 6, 2022, Vol. 375:6576, pp. 91-96)

CAR T cells target T cells and can be multiplied using cell culture techniques and reinfused into a patient to attack a specific cell type. The first CAR T-cell therapy was developed by researchers from UPenn and the Children's Hospital of Philadelphia. It was approved by the U.S. Food and Drug Administration in 2017 to treat certain leukemias, and later, it was approved for lymphoma.

Although CAR T-cell technology is currently used primarily to treat cancers, with dramatic results in many otherwise hopeless cases, its developers have long envisioned harnessing the approach for other diseases. Dr. Jonathan Epstein, chief scientific officer for Penn Medicine and executive vice dean and the William Wikoff Smith professor of cardiovascular research of the Perelman School of Medicine at UPenn, and colleagues showed in a 2019 study that the standard CAR T-cell approach can be used to attack overactive cardiac fibroblasts and restore heart function in a mouse model of heart failure.

In the current study, the authors generated modified nucleoside-containing mRNA, encoding a CAR designed against fibroblast activation protein (FAP) (a marker of activated fibroblasts) and packaging it in CD5-targeted T cell-targeted lipid nanoparticles (LNPs) (referred to as targeting antibody/LNP-mRNA cargo or CD5/LNP-FAPCAR).

These LNP-generated CAR T cells were able to effectively kill FAP-expressing target cells in vitro with 89% to 93% efficiency. Mice were injured to allow fibrosis to be established before injecting CD5/LNP-FAPCAR. Two days after LNP injection, authors found a consistent population of FAPCAR+ T cells (17.5%-24.7%) exclusively in mice that received CD5/LNP-FAPCAR.

The researchers also reported marked functional improvements in injured mice treated with in vivo-produced transient FAPCAR T cells. Injured mice treated with CD5/LNP-FAPCAR exhibited normalized left ventricular and end-diastolic volumes. Though body weight did not show statistically significant differences after CD5/LNP-FAPCAR injection, the trend in improvement compared with control mice was noted.

Injections of the mRNA in mice that modeled heart failure successfully reprogrammed a large population of mouse T cells, causing a major reduction of heart fibrosis and a restoration of mostly normal heart size and function with no evidence of continued antifibroblast 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.

Do you have a unique perspective on your research related to cell therapy? Contact the editor today to learn more.

---



New 'armed' CAR T cells can locally activate small-molecule cancer drugs
A new engineered CAR T platform, which turns cells into targeted “micropharmacies” with local activation of small-molecule prodrugs, has been shown to...
Can cell therapies treat cardiovascular disease?
While the development of cell therapies today is largely focused on oncology indications, some companies, including Athersys, envision a future where...
Precigen highlights results from UltraCAR-T trials
Precigen has released initial results from phase I studies of drugs included in its UltraCAR-T and AdenoVerse platforms.

Copyright © 2022 scienceboard.net


Conferences
International Society for Cell and Gene Therapy Annual Meeting
May 4 - June 7
San Francisco, California United States
American Society for Mass Spectrometry Annual Conference
June 5-9
Minneapolis, Minnesota United States
American Society for Microbiology Microbe Meeting
June 9-13
District of Columbia United States
HPLC 2022
June 18-23
San Diego, California United States
Connect
Science Advisory Board on LinkedIn
Science Advisory Board on Facebook
Science Advisory Board on Twitter