Sensitive manipulation of CAR T cell activity using a chimeric endocytosing receptor

Area of Science:

• Cellular and Molecular Biology
• Immunotherapy
• Biotechnology

Background:

• Adoptive cell therapies (ACTs) often lack post-transplantation control over therapeutic cell behavior.
• Existing methods to modulate ACTs are hampered by systemic drug toxicity, affecting non-target cells.

Purpose of the Study:

• To engineer a controllable system for modulating ACT activity post-infusion.
• To develop a method for selective drug targeting to engineered therapeutic cells.

Main Methods:

• Designed a two-domain fusion receptor with a ligand-binding domain and a constitutive recycling domain.
• Created ligand-drug conjugates targeting a ligand absent in humans for selective uptake by ACTs.
• Fused the endocytosing domain of human folate receptor alpha to murine scFv or human FK506 binding protein.

Main Results:

• Demonstrated selective internalization of ligand-drug conjugates into engineered ACTs.
• Successfully modulated CAR T cell activity in vitro and in vivo using the developed system.
• Achieved precise control, including downregulation or complete shutdown, of CAR T cell functions.

Conclusions:

• The 'chimeric endocytosing receptor' offers a versatile platform for controlling various ACTs.
• This technology is crucial for advancing ACT applications in treating diseases like cancer, diabetes, and sickle cell anemia.