Preventing trogocytosis by cathepsin B inhibition augments CAR T cell function

Area of Science:

• Immunotherapy
• Cancer Biology
• Cellular Mechanisms

Background:

• Chimeric antigen receptor (CAR) T cell therapy shows promise but suffers from patient relapse.
• CAR-mediated trogocytosis (CMT) is a proposed tumor escape mechanism leading to antigen loss and CAR T cell dysfunction.
• The precise role of CMT in CAR T cell failure and its underlying molecular drivers are not fully understood.

Purpose of the Study:

• To investigate if CMT directly causes CAR T cell dysfunction (fratricide and exhaustion).
• To identify the molecular mechanisms responsible for CMT.
• To explore therapeutic strategies targeting CMT to enhance CAR T cell efficacy.

Main Methods:

• Utilized a selective degrader to remove trogocytosed antigens from CAR T cells.
• Conducted a high-throughput small molecule screening assay to identify CMT regulators.
• Assessed CAR T cell fratricide, exhaustion, and persistence in relation to CMT and cathepsin B (CTSB) activity.

Main Results:

• Trogocytosed antigens on CAR T cells directly induce CAR T cell fratricide and exhaustion.
• The cysteine protease cathepsin B (CTSB) was identified as essential for CMT.
• Inhibition of CTSB effectively prevents CAR T cell fratricide and exhaustion, separating CMT from cytotoxic activity.

Conclusions:

• CMT is a direct cause of CAR T cell dysfunction and relapse.
• CTSB activity is critical for CMT and negatively impacts CAR T cell persistence.
• Targeting CTSB offers a potential strategy to improve CAR T cell therapy outcomes by enhancing CAR T cell persistence and efficacy.