Targeting fibroblast activation protein with chimeric antigen receptor macrophages

Area of Science:

• Immunotherapy
• Cellular Engineering
• Oncology
• Hepatology

Background:

• Chimeric antigen receptor T cell (CAR-T) technology is advancing rapidly.
• CAR-macrophages (CAR-Ms) are emerging as a new therapeutic strategy in pre-clinical stages.
• Fibroblast activation protein (FAP) is highly expressed in various cancers and fibrotic diseases.

Purpose of the Study:

• To construct FAP-targeted CAR macrophages (CAR-Ms).
• To evaluate the therapeutic potential of FAP-CAR-Ms in cancer and liver fibrosis models.

Main Methods:

• Constructed FAP-CAR macrophages for targeting FAP+ cells.
• Conducted in vitro phagocytosis assays.
• Performed in vivo studies using mouse subcutaneous MC38 colon cancer and CCl4-induced liver fibrosis models.

Main Results:

• FAP-CAR-ΔZETA bone marrow-derived macrophages (BMDMs) showed a pronounced anti-tumor effect in a mouse colon cancer model.
• Both FAP-CAR and FAP-CAR-ΔZETA BMDMs therapy improved CCl4-induced liver fibrosis in mice.
• FAP-CAR-Ms demonstrated efficacy in both cancer and liver fibrosis models.

Conclusions:

• FAP-CAR-Ms are a promising cellular therapy for FAP-expressing cancers.
• FAP-CAR-Ms also show therapeutic potential for fibrotic diseases like liver fibrosis.
• The FAP-CAR-ΔZETA construct exhibited superior anti-tumor activity compared to FAP-CAR in the tested model.