Defining an Optimal Dual-Targeted CAR T-cell Therapy Approach Simultaneously Targeting BCMA and GPRC5D to Prevent...

Area of Science:

• Immunotherapy
• Oncology
• Cellular Therapy

Background:

• CAR T-cell therapy targeting BCMA shows promise for multiple myeloma (MM).
• Relapse in MM after BCMA-targeted CAR T-cell therapy is often due to MM cells with low BCMA expression (antigen escape).

Purpose of the Study:

• To investigate dual-targeting CAR T-cell strategies to overcome BCMA antigen escape in MM.
• To compare the efficacy of different dual-targeted CAR T-cell designs.

Main Methods:

• Comparison of three dual-targeted CAR T-cell approaches: pooled mono-CAR T-cells, bicistronic CAR T-cells, and single-stalk dual-scFv CAR T-cells.
• Evaluation in a preclinical model of MM, focusing on BCMA-negative and dual-antigen-expressing disease.
• Assessment of efficacy at subtherapeutic doses.

Main Results:

• Bicistronic and pooled CAR T-cell approaches were most effective against BCMA-negative MM cells.
• The bicistronic approach showed superior efficacy compared to the pooled approach when targeting dual-antigen-expressing MM cells.
• Dual CAR expression on a single T-cell enhanced CAR T-cell/target cell interactions.

Conclusions:

• Simultaneous targeting of BCMA and GPRC5D can prevent BCMA escape-mediated relapse in MM.
• Bicistronic CAR T-cell constructs represent a promising strategy for overcoming antigen escape in MM treatment.