Desensitized chimeric antigen receptor T cells selectively recognize target cells with enhanced antigen expression

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T cell therapy shows promise for cancer treatment.
• CAR T cells engineered to target surface antigens can cause fratricide, limiting their therapeutic potential.
• Human leukocyte antigen-DR (HLA-DR) is a surface antigen expressed on certain cancer cells.

Purpose of the Study:

• To investigate the impact of CAR T cell affinity for HLA-DR on fratricide and therapeutic efficacy.
• To explore avidity tuning as a strategy to control CAR T cell activity and selectivity.
• To determine if desensitized CAR T cells can selectively eliminate cancer cells based on antigen expression levels.

Main Methods:

• Engineering CAR T cells to target human leukocyte antigen-DR (HLA-DR).
• Assessing CAR T cell fratricide and CAR downregulation in vitro.
• Evaluating CAR T cell desensitization and selective killing of Epstein-Barr virus-transformed B cells.
• Measuring CAR T cell avidity and antigen-sensing capabilities.

Main Results:

• Weak affinity CARs targeting HLA-DR significantly reduced CAR T cell fratricide.
• Sustained CAR downregulation led to CAR T cell desensitization.
• Desensitized CAR T cells selectively killed HLA-DR-expressing cancer cells while sparing normal cells.
• The study demonstrated an avidity-tuning strategy for CAR T cells.

Conclusions:

• Avidity tuning via weak CAR affinity is a viable strategy to mitigate CAR T cell fratricide.
• Desensitized CAR T cells exhibit enhanced selectivity for cancer cells based on antigen expression levels.
• This approach offers a novel way to control CAR T cell activity and improve therapeutic safety and efficacy.