Novel BCMA-OR-CD38 tandem-dual chimeric antigen receptor T cells robustly control multiple myeloma

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR)-T cell therapy targeting B-cell maturation antigen (BCMA) shows promise for multiple myeloma.
• Antigen escape and tumor relapse remain significant challenges limiting the long-term efficacy of BCMA-targeted CAR T-cell therapies.

Purpose of the Study:

• To develop and evaluate novel bispecific CAR T-cells targeting both BCMA and CD38 to overcome antigen escape in multiple myeloma.
• To assess the efficacy and safety of BCMA-OR-CD38 Tan CAR T-cells compared to single-target CAR T-cells.

Main Methods:

• Generation of BCMA-OR-CD38 tandem (Tan) CAR T-cells.
• In vitro assessment of CAR expression, cytotoxicity, and T-cell proliferation against BCMA- and/or CD38-expressing target cells.
• In vivo evaluation of tumor clearance and relapse in a mouse model of multiple myeloma.

Main Results:

• BCMA-OR-CD38 Tan CAR T-cells exhibited comparable CAR expression and superior cytotoxicity and proliferation compared to single-target CAR T-cells.
• Complete tumor eradication was achieved in myeloma-bearing mice, with no observed relapse.
• The BCMA-OR-CD38 Tan CAR T-cell construct is compatible with existing clinical T-cell manufacturing protocols.

Conclusions:

• BCMA-OR-CD38 Tan CAR T-cells offer a promising strategy to overcome antigen escape and improve therapeutic outcomes in multiple myeloma.
• This dual-targeting approach represents a viable solution for enhancing the durability of CAR T-cell therapy in relapsed/refractory multiple myeloma.