CAR Binders Affect CAR T-cell Tonic Signaling, Durability, and Sensitivity to Target.

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Murine CD19-specific single-chain variable fragments in CAR T cells can elicit anti-mouse immune responses.
• Developing fully human CAR T cells is crucial to mitigate immunogenicity and improve therapeutic outcomes.

Purpose of the Study:

• To identify and select fully human CD19 binders for CAR T cell therapy.
• To evaluate the efficacy and safety of novel fully human CAR T cells compared to existing therapies.

Main Methods:

• Screening of a yeast display library to identify fully human CD19 binders.
• In vitro and in vivo studies to assess CAR T cell function, including tumor killing and antigen recognition.
• Preclinical testing in a mouse model of acute lymphoblastic leukemia.

Main Results:

• Identified multiple fully human CD19 binders with varying CAR T cell performance characteristics.
• CAR T cells using binder 42 demonstrated robust anti-tumor activity and comparable efficacy to FMC63-based CAR T cells in vivo.
• Binder 42 CAR T cells showed non-inferiority to FMC63 CAR T cells in a mouse model of acute lymphoblastic leukemia.

Conclusions:

• Fully human CD19-specific CAR T cells using binder 42 offer a promising alternative to murine-based CAR T cells.
• Binder 42 CAR T cells exhibit comparable efficacy to established therapies and warrant further clinical investigation.
• This approach may overcome immunogenicity issues associated with current CAR T cell therapies.