Preclinical evaluation and structural optimization of anti-BCMA CAR to target multiple myeloma

Area of Science:

• Immunotherapy
• Oncology
• Cellular Engineering

Background:

• Chimeric antigen receptor (CAR) T-cell therapy shows promise for hematological malignancies.
• CD19-targeted CAR T-cells are successful, necessitating new targets for other cancers.
• B-cell maturation antigen (BCMA) is a key target for multiple myeloma (MM).

Purpose of the Study:

• To evaluate the function and optimal design of different BCMA-specific CAR constructs.
• To compare novel CAR configurations with a clinically used BCMA-CAR.
• To identify an improved CAR T-cell therapy for multiple myeloma.

Main Methods:

• Designed and constructed various BCMA-specific CARs with differing hinge and co-stimulatory domains.
• Expressed CAR constructs in primary human T cells.
• Assessed CAR T-cell function, including cytokine production, cytotoxicity, activation markers, and exhaustion.
• Evaluated in vivo anti-tumoral activity in preclinical models.

Main Results:

• All CAR constructs showed high expression and triggered anti-myeloma activity.
• Significant differences observed in off-target activation, T-cell exhaustion, and activation marker expression.
• A CAR design utilizing a CD8-based hinge and 4-1BB co-stimulatory domain (H8BB) outperformed other configurations.
• H8BB CAR demonstrated superior in vitro and long-term in vivo anti-tumoral efficacy.

Conclusions:

• The primary structure of CARs critically influences their function and efficacy.
• The novel H8BB CAR exhibits enhanced anti-myeloma activity compared to existing designs.
• H8BB CAR represents a promising therapeutic candidate for multiple myeloma treatment.