Fibroblast Activation Protein-Targeted CAR-T Cells Induce Apoptosis in Murine Cardiac Myofibroblasts.

Area of Science:

• Cardiovascular Research
• Immunotherapy
• Cellular Biology

Background:

• Myocardial fibrosis is a significant factor in cardiovascular diseases, lacking targeted therapies.
• Chimeric antigen receptor T (CAR-T) cell therapy shows potential beyond oncology.
• Fibroblast activation protein (FAP) is identified as a viable therapeutic target.

Purpose of the Study:

• To engineer and evaluate fibroblast activation protein (FAP)-targeted CAR-T cells for potential cardiac fibrosis treatment.
• To assess the safety and efficacy of a second-generation FAP-CAR construct with a 4-1BB costimulatory domain.
• To investigate FAP-CAR Jurkat cells as a preliminary model for fibrosis-selective cytotoxicity.

Main Methods:

• Engineered second-generation FAP-targeted CAR constructs with a 4-1BB costimulatory domain.
• Utilized lentiviral vectors and lipid nanoparticles (LNPs) for delivery.
• Generated and evaluated FAP-CAR-engineered Jurkat cells for CAR expression, target recognition, and in vitro cytotoxicity against FAP-expressing cardiac myofibroblasts.

Main Results:

• FAP-CAR-engineered Jurkat cells demonstrated selective recognition and apoptosis induction in FAP-expressing cardiac myofibroblasts.
• Engineered cells did not induce excessive interleukin-6 (IL-6) secretion, suggesting improved safety.
• Preliminary in vitro data support the target-specific functionality of FAP-targeted CAR constructs with the 4-1BB domain.

Conclusions:

• FAP-targeted CAR constructs incorporating the 4-1BB domain show preliminary in vitro efficacy for fibrosis-selective cytotoxicity.
• These findings warrant further investigation in primary T cell models for cardiac fibrosis therapy.
• The engineered CAR-T cells present a potential novel therapeutic strategy for cardiovascular diseases characterized by fibrosis.