Preclinical development of a humanized chimeric antigen receptor against B cell maturation antigen for multiple...

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Multiple myeloma (MM) is an incurable hematological malignancy.
• Chimeric antigen receptor (CAR)-T cell therapy is effective for relapsed/refractory B cell malignancies.
• B-cell maturation antigen (BCMA) is a promising target for MM immunotherapy.

Purpose of the Study:

• To develop and evaluate a novel CAR-T cell therapy targeting BCMA for multiple myeloma.
• To humanize murine CAR-T cells to reduce immunogenicity and improve safety.
• To assess the efficacy and toxicity of humanized CAR-T cells in preclinical models.

Main Methods:

• Generation of clinical-grade murine CAR-T cells targeting BCMA (ARI2m cells).
• Humanization of the single chain variable fragment to create ARI2h cells.
• In vitro and in vivo efficacy and toxicity assessments.
• Large-scale cell expansion under Good Manufacturing Practice (GMP) guidelines.
• Investigation of soluble BCMA and vesicle-impact on CAR-BCMA activity.

Main Results:

• ARI2h cells showed comparable efficacy to ARI2m cells in vitro and in vivo.
• ARI2h cells demonstrated superior efficacy in high tumor burden models.
• ARI2h cells exhibited lower TNFα production and reduced in vivo toxicity.
• Successful large-scale GMP-compliant expansion of CAR-T cells was achieved.
• Soluble BCMA and BCMA-containing vesicles were found to impact CAR-BCMA activity.

Conclusions:

• Humanized BCMA-targeted CAR-T cells (ARI2h) are a promising therapeutic candidate for multiple myeloma.
• ARI2h cells offer potential advantages in terms of reduced immunogenicity and toxicity.
• The study provides a strong preclinical basis for initiating a clinical trial in multiple myeloma patients.
• Understanding the impact of soluble BCMA is crucial for optimizing CAR-T cell therapy.